MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Human Mutation' source. Thu, 09 Feb 2012 09:43:39 +0100 http://www.medworm.com/index.php?rid=5672468&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22032 In this study we assess exome sequencing (ES) as a diagnostic alternative for genetically heterogeneous disorders. Since ES readily identified a previously reported homozygous mutation in the CAPN3 gene for an individual with an undiagnosed limb girdle muscular dystrophy, we evaluated ES as a generalizable clinical diagnostic tool by assessing the targeting efficiency and sequencing‐coverage of 88 genes associated with muscle disease (MD) and spastic paraplegia (SPG). We used three exome‐capture kits on 125 individuals. Exons constituting each gene were defined using the UCSC and CCDS databases. The three exome‐capture kits targeted 47‐92% of bases within the UCSC‐defined exons, and 97%‐99% of bases within the CCDS‐defined exons. An average of 61.2‐99.5% and 19.1‐99.5% of... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5672468 Wed, 01 Feb 2012 05:00:00 +0100 5672468 http://www.medworm.com/index.php?rid=5654723&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22033 AbstractDisease gene discovery has been transformed by affordable sequencing of exomes and genomes. Identification of disease‐causing mutations requires sifting through a large number of sequence variants. A subset of the variants are unlikely to be good candidates for disease causation based on one or more of the following criteria: (1) being located in genomic regions known to be highly polymorphic, (2) having characteristics suggesting assembly misalignment, and/or (3) being labeled as variants based on misleading reference genome information. We analyzed exome sequence data from 118 individuals in 29 families seen in the NIH Undiagnosed Diseases Program (UDP) to create lists of variants and genes with these characteristics. Specifically, we identified several groups of genes that are... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654723 Wed, 01 Feb 2012 05:00:00 +0100 5654723 http://www.medworm.com/index.php?rid=5642446&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22036 AbstractTarget enrichment strategies are a very common approach to sequence a predefined part of an individual's genome using second‐generation sequencing technologies. While highly dependent on the technology and the target sequences selected, the performance of the various assays is variable also between samples and influenced by the way how the libraries are handled in the laboratory. Here, we show how we find detailed information about the enrichment performance using a novel software package called NGSrich which we developed as part of a whole‐exome resequencing pipeline in a medium‐sized genomics center. Our software is suitable for high‐throughput use and the results can be shared using HTML and a webserver. Finally, we have sequenced exome‐enriched DNA libraries of 18 hum... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5642446 Mon, 30 Jan 2012 18:00:52 +0100 5642446 http://www.medworm.com/index.php?rid=5654728&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22034 AbstractThe analysis of variants generated by exome sequencing of families with rare Mendelian diseases is a time‐consuming, manual process that represents one barrier to applying the technology routinely. To address this issue, we have developed a software tool, VAR‐MD (http://research.nhgri.nih.gov/software/var‐md/), for analyzing the DNA sequence variants produced by human exome sequencing. VAR‐MD generates a ranked list of variants using predicted pathogenicity, Mendelian inheritance models, genotype quality and population variant frequency data. VAR‐MD was tested using two previously solved data sets and one unsolved data set. In the solved cases, the correct variant was listed at the top of VAR‐MD's variant ranking. In the unsolved case, the correct variant was highly ran... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654728 Mon, 30 Jan 2012 05:00:00 +0100 5654728 http://www.medworm.com/index.php?rid=5654727&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22037 We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and consequently which of the three major SOX5 protein isoforms are affected. One intragenic deletion involving only untranslated exons was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, som... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654727 Mon, 30 Jan 2012 05:00:00 +0100 5654727 http://www.medworm.com/index.php?rid=5654726&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22038 AbstractNumerous mismatch repair (MMR) gene variants have been identified in Lynch syndrome and other cancer patients, but knowledge about their pathogenicity is frequently missing. The diagnosis and treatment of patients would benefit from knowing which variants are disease‐related. Bioinformatic approaches are well suited to the problem and can handle large numbers of cases. Functional effects were revealed based on literature for 168 MMR missense variants. Performance of numerous prediction methods was tested with this dataset. Among the tested tools only the results of tolerance prediction methods correlated to functional information, however with poor performance. Therefore a novel consensus based predictor was developed. The novel prediction method, PON‐MMR, achieved accuracy of ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654726 Mon, 30 Jan 2012 05:00:00 +0100 5654726 http://www.medworm.com/index.php?rid=5654725&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22040 AbstractGenome‐wide associations with glycosylated hemoglobin, which reflects the long‐term glycemia, were examined using two independent cohorts of the Korea Association Resource (KARE) consortium. We first identified sequence variants within a linkage disequilibrium block (r2 > 0.98) in the intron 5 of cyclin‐dependent kinase 5 regulatory subunit‐associated protein 1‐like 1 (CDKAL1) gene using 4,275 normoglycemic subjects of Cohort 1 (P < 2.5×10−8). The association was replicated in 3,782 normoglycemic subjects of Cohort 2. Furthermore, the sequence variants were also associated with glucose levels after oral glucose tolerance test. Especially, a strong association with 1 h glucose (P = 1.3×10−11) led us to interpreting that CDKAL1 might influence the level of glyco... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654725 Mon, 30 Jan 2012 05:00:00 +0100 5654725 http://www.medworm.com/index.php?rid=5654724&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22041 AbstractThe multidrug resistance protein 2 (MRP2/ABCC2) is involved in the efflux of endogenous and xenobiotic substrates, including several anticancer and antiviral drugs. The functional consequences of ABCC2 protein variants remain inconsistent, which may be due to shortcomings of the in vitro assays used. To study systematically the functional consequences of nonsynonymous ABCC2 variants, we used a novel “Screen and Insert” (ScIn) technology to achieve stable and highly reproducible expression of thirteen ABCC2 variants in HT1080 cells. Western blotting revealed lower (30‐65%) ABCC2 expression for D333G, R1174H, and R1181L as compared to wild‐type (100%), whereas the linked variant V1188E/C1515Y resulted in higher expression (150%). R1174H caused mislocalization of ABCC2 to the ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654724 Mon, 30 Jan 2012 05:00:00 +0100 5654724 http://www.medworm.com/index.php?rid=5642448&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22035 We present the results of our experience with over 30 families for whom HTS sequencing was used in an attempt to find clinical diagnoses. For each family, exome sequence was augmented with high‐density SNP‐array data. We present a discussion of the theory and practical application of each analytic step and provide example data to illustrate our approach. The paper is designed to provide an analytic roadmap for variant analysis, thereby enabling a wide range of researchers and clinical genetics practitioners to perform direct analysis of HTS data for their patients and projects. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5642448 Mon, 30 Jan 2012 05:00:00 +0100 5642448 http://www.medworm.com/index.php?rid=5642447&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22031 AbstractThe FCGR locus encoding the low‐affinity Fcγ receptors for IgG has largely been missed by genome‐wide association studies due to complications with structural variation and segmental duplication. Recently identified CNVs affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant (QSV) assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy controls (n=1115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of fa... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5642447 Mon, 30 Jan 2012 05:00:00 +0100 5642447 http://www.medworm.com/index.php?rid=5615668&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22028 We report the identification of two missense SEPT12 mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, in infertile men. Both mutations are located inside the GTPase domain and may alter the protein structure as suggested by in silico modeling. The p.Thr89Met mutation (SEPT12T89M) significantly reduced GTP hydrolytic activity, and the p.Asp197Asn mutation (SEPT12D197N) interfered with GTP binding. Both mutant SEPT12 proteins restricted the filament formation of the wild‐type SEPT12 in a dose‐dependent manner. The patient carrying SEPT12D197N presented with oligo‐asthenozoospermia while the SEPT12T89M patient had astheno‐teratozoospermia. The characteristic sperm pathology of the SEPT12D197N patient included defective annulus with bent tail and loss of SEPT12 from the an... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5615668 Sat, 21 Jan 2012 14:25:08 +0100 5615668 http://www.medworm.com/index.php?rid=5615671&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22030 AbstractCongenital cardiovascular malformation (CVM) exhibits familial predisposition but most of the specific genetic factors involved are unknown. Postulating that rare variants in genes in critical cardiac developmental pathways predispose to CVM, we systematically surveyed three genes of the bone morphogenetic protein (BMP) signalling pathway for novel variants. Exonic, splice site and untranslated regions of BMPR1A, BMPR2 and SMAD6 genes were sequenced in 90 unrelated sporadic cases of CVM. One non‐synonymous variant (p.C484F) with predicted functional impact was found in the MAD homology 2 (MH2) domain of SMAD6, an intracellular inhibitor of BMP signalling. Sequencing this domain in an additional 346 cases of CVM yielded two further non‐synonymous variants (p.P415L and p.A325T). ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5615671 Fri, 20 Jan 2012 05:00:00 +0100 5615671 http://www.medworm.com/index.php?rid=5615670&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22029 AbstractPCDH19 encodes protocadherin 19 on chromosome Xq22.3. This 1148 amino‐acid protein, highly expressed during brain development, could play significant roles in neuronal migration or establishment of synaptic connections. PCDH19 is composed of 6 exons, with a large first exon encoding the entire extracellular domain of the protein. Heterozygous PCDH19 mutations were initially identified in epilepsy and mental retardation limited to females, a familial disorder with a singular mode of inheritance since only heterozygous females are affected whereas hemizygous males are asymptomatic. Yet, mosaic males can also be affected, supporting cellular interference as the pathogenic mechanism. Recently, mutations in PCDH19, mostly occurring de novo, were shown to be a frequent cause of sporadi... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5615670 Fri, 20 Jan 2012 05:00:00 +0100 5615670 http://www.medworm.com/index.php?rid=5615669&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22027 AbstractWe evaluated an autopsy case with severe neonatal respiratory distress, hypoplasia of thymus, thyroid gland and cerebellum, and agenesis of the corpus callosum displaying striking phenotypic similarity to the CrebA knockout mouse. On the assumption that comparable genetic alterations must be present, we checked the whole genomic DNA sequence of CREB1, the human counterpart of mouse CrebA, and found a missense c.347A>G mutation corresponding to p.D116G within the kinase inducible domain (KID) of CREB1. When transcribed in vitro, while Ser133‐phosphorylation of KID was maintained upon forskolin treatment, mutated CREB1 protein failed to associate with the KIX domain of coactivator CREBBP/EP300, and thereby, interrupted cAMP‐dependent protein kinase (PKA) signal transduction as... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5615669 Fri, 20 Jan 2012 05:00:00 +0100 5615669 http://www.medworm.com/index.php?rid=5602644&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22026 AbstractNoonan syndrome (NS) is among the most common non‐chromosomal disorders affecting development and growth. NS is genetically heterogeneous, being caused by germline mutations affecting various genes implicated in the RAS signaling network. This network transduces extracellular signals into intracellular biochemical and transcriptional responses controlling cell proliferation, differentiation, metabolism, and senescence. To explore the transcriptional consequences of NS‐causing mutations, we performed global mRNA expression profiling on peripheral blood mononuclear cells obtained from 23 NS patients carrying heterozygous mutations in PTPN11 or SOS1. Gene expression profiling was also resolved in 5 subjects with Noonan‐like syndrome with loose anagen hair (NS/LAH), a condition c... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5602644 Wed, 18 Jan 2012 15:28:17 +0100 5602644 http://www.medworm.com/index.php?rid=5602646&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22024 AbstractThe fourth Personal Genomes meeting was held at Cold Spring Harbor Laboratory, New York, from 30 September to 2 October and provided an exciting collection of science built on recent significant milestones in individual human genome sequencing, from the first personal genomes to thousands of human genomes sequenced. As ultra‐high throughput sequencing platforms enable the production of more and more individual genomes, a growing number of scientists, physicians and clinical geneticists are actively exploring the promise and the implications of these new data. Personal Genomes brought many of these pioneers together with nearly 200 scientists, physicians, ethicists and others to discuss the progress and opportunities around the sequencing and medical interpretation of individual g... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5602646 Tue, 17 Jan 2012 05:00:00 +0100 5602646 http://www.medworm.com/index.php?rid=5602645&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22025 AbstractGermline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome‐wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four SNPs, rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31) and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per‐allele hazard ratio (HR) = 0.81 (95%CI: 0.67‐0.98) P‐trend = 0.033, rs2665... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5602645 Tue, 17 Jan 2012 05:00:00 +0100 5602645 http://www.medworm.com/index.php?rid=5590910&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22006 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5590910 Sun, 15 Jan 2012 03:44:24 +0100 5590910 http://www.medworm.com/index.php?rid=5590906&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22568 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5590906 Sun, 15 Jan 2012 03:43:53 +0100 5590906 http://www.medworm.com/index.php?rid=5590900&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22022 AbstractGermline mutations in the PALB2 gene are associated with an increased risk of developing breast but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (p = 0.04). The first degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of non‐carrier cases, indicating that pathogenic P... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5590900 Sun, 15 Jan 2012 03:43:21 +0100 5590900 http://www.medworm.com/index.php?rid=5590902&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22021 In this study, we report differential miRNA expression in IBD patients with associated CRC, from non‐neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were up‐regulated from non‐neoplastic tissue to dysplasia, but down‐regulated from dysplasia to cancer (miR‐122, miR‐181a, miR‐146b‐5p, let‐7e, miR‐17, miR‐143) (p < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR‐122, miR‐214, miR‐372, miR‐15b, let‐7e, miR‐17) (p < 0.001). Using two human colon cancer cell lines (HT‐29 and HCT‐116), E2F1, an upstream regulator of TP53, was down‐regulated in both cell lines transfected with let‐7e (p < 0.05) ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5590902 Thu, 12 Jan 2012 05:00:00 +0100 5590902 http://www.medworm.com/index.php?rid=5590901&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22023 This study shows that a variety of mitochondrial genes, including protein coding genes, can be responsible for non‐syndromic deafness, and that exposure to aminoglycosides is not required to develop the disease, giving new insights on the molecular bases of this pathology. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5590901 Thu, 12 Jan 2012 05:00:00 +0100 5590901 http://www.medworm.com/index.php?rid=5556122&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22020 AbstractRenal coloboma syndrome, also known as papillorenal syndrome is an autosomal dominant disorder characterized by ocular and renal malformations. Mutations in the paired‐box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556122 Sun, 01 Jan 2012 05:00:00 +0100 5556122 http://www.medworm.com/index.php?rid=5654730&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22018 AbstractThe 2011 annual scientific meeting of the Human Genome Variation Society (HGVS) was held on the 11th of October, in Montreal, Canada. The theme of this meeting was “Exome and Genome Analysis as a Tool for Disease Identification and Treatment.” In the last few years, there has been a substantial increase in the use of next‐generation sequencing in identifying variants associated with both single‐gene disorders and complex diseases. The advent of exome sequencing with the subsequent transition to whole genome sequencing will require methods to identify candidate causal variants both in coding and regulatory regions. As this technology slowly moves into the clinical diagnostic laboratory, the need to accurately predict the functional consequences of variants becomes more criti... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654730 Thu, 29 Dec 2011 05:00:00 +0100 5654730 http://www.medworm.com/index.php?rid=5654729&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22020 AbstractRenal coloboma syndrome, also known as papillorenal syndrome is an autosomal‐dominant disorder characterized by ocular and renal malformations. Mutations in the paired‐box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus‐specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participa... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5654729 Thu, 29 Dec 2011 05:00:00 +0100 5654729 http://www.medworm.com/index.php?rid=5633821&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22016 AbstractAtaxia‐telangiectasia (A‐T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A‐T mutated (ATM) gene. To study genotype–phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A‐T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X‐ray hypersensitivity in lym... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5633821 Thu, 29 Dec 2011 05:00:00 +0100 5633821 http://www.medworm.com/index.php?rid=5556127&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22015 This article presents for the first time a comprehensive analysis of the dysferlin mutational spectrum based on all compiled DYSF disease‐causing mutations reported in the literature to date, and using the main bioinformatics tools offered in UMD‐DYSF. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556127 Thu, 29 Dec 2011 05:00:00 +0100 5556127 http://www.medworm.com/index.php?rid=5556126&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22017 We present the design and experimental validation of a new, simple and easy‐to‐use platform we call FluiDMD. This platform is based on the Applied Biosystems 7900HT TaqMan® Low‐Density Array technology and is able to define the full exon composition, profile the dystrophin isoforms present, establish changes in mRNA decay, and potentially identify all deletions/duplications and splicing‐affecting mutations contemporaneously. Moreover, we demonstrate that this system accurately detects the pathogenic effect of all dystrophin mutations belonging to any category, thereby highlighting the functional validation capacity of this system. The high efficacy and sensitivity of this tool in detecting mutations in the dystrophin transcript can be exploited in a variety of cells/tissues, in pa... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556126 Thu, 29 Dec 2011 05:00:00 +0100 5556126 http://www.medworm.com/index.php?rid=5556125&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22016 AbstractAtaxia‐telangiectasia (A‐T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A‐T mutated (ATM) gene. To study genotype‐phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A‐T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X‐ray hypersensitivity in lym... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556125 Thu, 29 Dec 2011 05:00:00 +0100 5556125 http://www.medworm.com/index.php?rid=5556124&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22019 AbstractCongenital Disorders of Glycosylation comprise a clinically and biochemically heterogeneous group of monogenetic inherited, multisystemic diseases that affect the biosynthesis of N‐ and/or O‐glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic orientated GDP‐mannose:Man3‐4GlcNAc2‐PP‐dolichol alpha‐1,2‐mannosyltransferase (ALG11), who presented with an accumulation of shortened dolichol‐linked oligosaccharides leading to Congenital Disorder of Glycosylation‐Ip (CDG‐Ip; ALG11‐CDG). Here we describe an improved metabolic labelling method that allowed the identification of three new CDG‐Ip cases which were missed so far in routine diagnostics. Although all CDG‐Ip patients carry different mutations in the... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556124 Thu, 29 Dec 2011 05:00:00 +0100 5556124 http://www.medworm.com/index.php?rid=5556123&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22018 AbstractThe 2011 annual scientific meeting of the Human Genome Variation Society (HGVS) was held on the 11th of October, in Montreal, Canada. The theme of this meeting was “Exome & Genome Analysis as a Tool for Disease Identification and Treatment”. In the last few years, there has been a substantial increase in the use of next generation sequencing in identifying variants associated with both single gene disorders and complex diseases. The advent of exome sequencing with the subsequent transition to whole genome sequencing will require methods to identify candidate causal variants both in coding and regulatory regions. As this technology slowly moves into the clinical diagnostic laboratory, the need to accurately predict the functional consequences of variants becomes more critica... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556123 Thu, 29 Dec 2011 05:00:00 +0100 5556123 http://www.medworm.com/index.php?rid=5531290&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22013 AbstractType‐2 NF1 deletions spanning 1.2‐Mb are frequently of postzygotic origin and hence tend to be associated with mosaicism for normal cells and those harbouring the deletion (del(+/−) cells). Eleven patients with mosaic type‐2 deletions were investigated by FISH and high proportions (94‐99%) of del(+/−) cells were detected both in whole blood and in isolated CD3+, CD14+, CD15+ and CD19+ leukocytes. Significantly lower proportions of del(+/−) cells (24‐82%) were however noted in urine‐derived epithelial cells. A patient harbouring an atypical large NF1 deletion with non‐recurrent breakpoints was also found to have a much higher proportion of del(+/−) cells in blood (96%) than in urine (51%). The tissue‐specific differences in the proportions of del(+/−) cells... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531290 Fri, 23 Dec 2011 03:31:08 +0100 5531290 http://www.medworm.com/index.php?rid=5531291&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22014 In this study, we discovered a novel mechanism of CD274 expression regulated by miR‐570. A guanine‐to‐cytosine mutation at the 3′‐UTR of CD274 mRNA led to CD274 over‐expression by disrupting the miR‐570 binding. The mutations were widely observed in cancers by sequencing of 276 gastrointestinal cancers (esophageal, gastric, colorectal, hepatocellular, and pancreatic cancers). This mutation was significantly associated with CD274 over‐expression in gastric cancer (p = 1.44 × 10−10) and with the pathological features including differentiation grade, depth of tumor invasion, lymph node metastasis, and TNM stage. These studies suggest a novel regulatory mechanism for CD274 over‐expression in gastric cancer mediated by miR‐570 and a somatic mutation in CD274 3′‐UTR, a... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531291 Wed, 21 Dec 2011 05:00:00 +0100 5531291 http://www.medworm.com/index.php?rid=5531294&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22009 AbstractGenome‐wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2586 Swedes and performed gene‐based meta‐analysis with three additional studies from France, Canada, and the United States, in total encompassing 4259 cases and 8284 controls. Implementing a newly designed gene‐based algorithm, we identified two loci apart from the region around APOE that achieved study‐wide significance in combined samples, ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531294 Tue, 20 Dec 2011 05:00:00 +0100 5531294 http://www.medworm.com/index.php?rid=5531293&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22010 In conclusion, hOE‐MSCs isolated from FD patients represent a promising avenue for modeling the altered genetic expression of FD, demonstrating a methodology that can be applied to a host of other genetic disorders to test the therapeutic potential of candidate molecules. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531293 Tue, 20 Dec 2011 05:00:00 +0100 5531293 http://www.medworm.com/index.php?rid=5531292&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22012 AbstractDominant missense mutations in FLNB, encoding the actin‐cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin‐binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full‐length FLNB constructs containing ABD mutations resulted in the appearance of actin‐containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531292 Tue, 20 Dec 2011 05:00:00 +0100 5531292 http://www.medworm.com/index.php?rid=5510713&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21657 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5510713 Sat, 17 Dec 2011 02:53:16 +0100 5510713 http://www.medworm.com/index.php?rid=5510712&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22567 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5510712 Sat, 17 Dec 2011 02:53:15 +0100 5510712 http://www.medworm.com/index.php?rid=5510711&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22566 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5510711 Sat, 17 Dec 2011 02:53:14 +0100 5510711 http://www.medworm.com/index.php?rid=5510710&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22008 AbstractThe 12th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2011: Berkeley, California, USA, 8th–10th September 2011) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included progress beyond GWAS, variation in human populations, use of sequence data in medical settings, large‐scale sequencing data analysis, and bioinformatics approaches to large datasets. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5510710 Sat, 17 Dec 2011 02:52:39 +0100 5510710 http://www.medworm.com/index.php?rid=5499908&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22005 In this study, 96 disease‐associated sequence variants were identified in 130 unrelated alpha‐mannosidosis patients from 30 countries. Eighty three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a fe... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5499908 Mon, 12 Dec 2011 05:00:00 +0100 5499908 http://www.medworm.com/index.php?rid=5499907&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22007 AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Previously, we demonstrated that pathogenic amino acid substitutions in the N‐terminal domain of TSC1 (amino acids 50–224) are destabilising. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified 4 substitutions (p.L61R, p.G132D, p.F158S and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1‐TSC2‐dependent inhibition of TORC1. In 4 cases (20%) our functional assessment did not agree with the predictions of the SIFT amino acid substitution an... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5499907 Thu, 01 Dec 2011 05:00:00 +0100 5499907 http://www.medworm.com/index.php?rid=5481681&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22004 We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31 showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98 or DFNB31, showed... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5481681 Thu, 01 Dec 2011 05:00:00 +0100 5481681 http://www.medworm.com/index.php?rid=5453123&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22003 AbstractChronic granulomatous disease (CGD) is mainly caused by mutations in X‐linked CYBB which encodes gp91phox. We have identified two novel mutations in CYBB resulting in the rare X91+‐CGD variant, c.1500T>G (p.Asp500Glu) in two male siblings and c.1463C>A (p.Ala488Asp) in an unrelated male. Zymosan and/or PMA‐induced recruitment of p47phox and p67phox to the membrane fraction was normal for both mutants. Cell‐free assays using recombinant wild type and the mutant proteins revealed that these mutants were not activated by NADPH. Interestingly, the Ala488Asp mutant was activated by NADPH in the presence of glutathione. These data suggest that the mutations prevented NADPH from binding to gp91phox and the requirement of a negative charge at residue 500 in gp91phox for NADPH... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5453123 Tue, 29 Nov 2011 03:17:25 +0100 5453123 http://www.medworm.com/index.php?rid=5567115&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22003 AbstractChronic granulomatous disease (CGD) is mainly caused by mutations in X‐linked CYBB that encodes gp91. We have identified two novel mutations in CYBB resulting in the rare X91+‐CGD variant, c.1500T>G (p.Asp500Glu) in two male siblings and c.1463C>A (p.Ala488Asp) in an unrelated male. Zymosan and/or PMA (Phorbol 12‐myristate 13‐acetate)‐induced recruitment of p47phox and p67phox to the membrane fraction was normal for both mutants. Cell‐free assays using recombinant wild‐type and the mutant proteins revealed that these mutants were not activated by NADPH (nicotinamide adenine dinucleotide phosphate). Interestingly, the Ala488Asp mutant was activated by NADPH in the presence of glutathione. These data suggest that the mutations prevented NADPH from binding to gp91p... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5567115 Mon, 28 Nov 2011 05:00:00 +0100 5567115 http://www.medworm.com/index.php?rid=5556128&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22002 In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39, and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form. Hum Mutat 00:1–4, 2011. © 2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5556128 Mon, 28 Nov 2011 05:00:00 +0100 5556128 http://www.medworm.com/index.php?rid=5453125&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21649 This study illustrates the importance of high‐resolution array‐Comparative Genomic Hybridization analysis in exploring the potential role of disease‐causing mutation in functional noncoding sequences. Hum Mutat 00:1–4, 2011. © 2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5453125 Mon, 28 Nov 2011 05:00:00 +0100 5453125 http://www.medworm.com/index.php?rid=5453124&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22002 In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39 and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5453124 Mon, 28 Nov 2011 05:00:00 +0100 5453124 http://www.medworm.com/index.php?rid=5426989&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22001 AbstractPrimary ciliary dyskinesia (PCD) is an inherited disorder causing significant upper and lower respiratory tract morbidity and impaired fertility. Half of PCD patients show abnormal situs. Human disease loci have been identified but a mouse model without additional deleterious defects is elusive. The inversus viscerum mouse,mutated at the outer arm dynein heavy chain 11 locus (Dnahc11) is a known model of heterotaxy. We demonstrated immotile tracheal cilia with normal ultrastructure and reduced sperm motility in the Dnahc11iv mouse. This is accompanied by gross rhinitis, sinusitis and otitis media, all indicators of human PCD. Strikingly, age related progression of the disease is evident. The Dnahc11iv mouse is robust, lacks secondary defects and requires no intervention to precipit... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5426989 Sun, 20 Nov 2011 02:56:26 +0100 5426989 http://www.medworm.com/index.php?rid=5426990&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.22000 AbstractLynch Syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these Variants of Uncertain Significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell‐free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5426990 Fri, 18 Nov 2011 05:00:00 +0100 5426990 http://www.medworm.com/index.php?rid=5415624&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21638 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5415624 Thu, 17 Nov 2011 17:29:53 +0100 5415624 http://www.medworm.com/index.php?rid=5415623&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21637 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5415623 Thu, 17 Nov 2011 17:29:52 +0100 5415623 http://www.medworm.com/index.php?rid=5415620&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21660 AbstractAutosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL‐C levels below the 50 percentile for age and gender prior to lipid‐lowering therapy. The genes encoding APOB, PCSK9 and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss‐of‐function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in 5 (6.7%) probands, reducing LDL‐C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholestero... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5415620 Thu, 17 Nov 2011 17:28:53 +0100 5415620 http://www.medworm.com/index.php?rid=5531295&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21661 AbstractAutosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin–angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin‐converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two‐thirds of families (64.6%)... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531295 Thu, 17 Nov 2011 05:00:00 +0100 5531295 http://www.medworm.com/index.php?rid=5491461&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21663 AbstractLong INterspersed Element‐1 (LINE‐1) retrotransposons comprise 17% of the human genome, and move by a potentially mutagenic “copy and paste” mechanism via an RNA intermediate. Recently, the retrotransposition‐mediated insertion of a new transcript was described as a novel cause of genetic disease, Duchenne muscular dystrophy, in a Japanese male. The inserted sequence was presumed to derive from a single‐copy, noncoding RNA transcribed from chromosome 11q22.3 that retrotransposed into the dystrophin gene. Here, we demonstrate that a nonreference full‐length LINE‐1 is situated in the proband and maternal genome at chromosome 11q22.3, directly upstream of the sequence, whose copy was inserted into the dystrophin gene. This LINE‐1 is highly active in a cell culture as... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5491461 Thu, 17 Nov 2011 05:00:00 +0100 5491461 http://www.medworm.com/index.php?rid=5426993&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21661 AbstractAutosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin‐angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin‐converting enzyme) and AGTR1 (angiotensin II receptor type 1). Here we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two thirds of families (64.6%). The... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5426993 Thu, 17 Nov 2011 05:00:00 +0100 5426993 http://www.medworm.com/index.php?rid=5426992&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21662 AbstractCraniorachischisis is a severe neural tube defect (NTD) resulting from failure to initiate closure, leaving the hindbrain and spinal neural tube entirely open. Clues to the genetic basis of this condition come from several mouse models, which harbour mutations in core members of the planar cell polarity (PCP) signalling pathway. Previous studies of humans with craniorachischisis failed to identify mutations in the core PCP genes VANGL1 and VANGL2. Here we analysed other key PCP genes: CELSR1, PRICKLE1, PTK7 and SCRIB, with the finding of eight potentially causative mutations in both CELSR1 and SCRIB. Functional effects of these unique or rare human variants were evaluated using known protein‐protein interactions as well as subcellular protein localisation. While protein interacti... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5426992 Thu, 17 Nov 2011 05:00:00 +0100 5426992 http://www.medworm.com/index.php?rid=5426991&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21663 AbstractLong INterspersed Element‐1 (LINE‐1) retrotransposons comprise 17% of the human genome, and move by a potentially mutagenic “copy and paste” mechanism via an RNA intermediate. Recently, the retrotransposition‐mediated insertion of a new transcript was described as a novel cause of genetic disease, Duchenne muscular dystrophy, in a Japanese male. The inserted sequence was presumed to derive from a single‐copy, non‐coding RNA transcribed from chr. 11q22.3 that retrotransposed into the dystrophin gene. Here we demonstrate that a non‐reference full‐length LINE‐1 is situated in the proband and maternal genome at chr. 11q22.3, directly upstream of the sequence, whose copy was inserted into the dystrophin gene. This LINE‐1 is highly active in a cell culture assay. LI... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5426991 Thu, 17 Nov 2011 05:00:00 +0100 5426991 http://www.medworm.com/index.php?rid=5548753&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21658 AbstractVax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first descr... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5548753 Wed, 16 Nov 2011 05:00:00 +0100 5548753 http://www.medworm.com/index.php?rid=5531296&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21660 AbstractAutosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL‐cholesterol (LDL‐C) levels below the 50th percentile for age and gender prior to lipid‐lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss‐of‐function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL‐C by 56%. Rare variants in PCSK9, and ANGPTL3 completely corr... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531296 Wed, 16 Nov 2011 05:00:00 +0100 5531296 http://www.medworm.com/index.php?rid=5415622&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21658 AbstractVax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia. In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5415622 Wed, 16 Nov 2011 05:00:00 +0100 5415622 http://www.medworm.com/index.php?rid=5415621&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21659 AbstractSarcoglycanopathies are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (α‐, β‐, γ‐ and δ‐sarcoglycan) form a tetrameric complex at the muscle membrane that is part of the dystrophin‐glycoprotein complex and plays an essential role for membrane integrity during muscle contractions. We previously showed that the most frequent missense mutation in α‐sarcoglycan (p.R77C) leads to the absence of the protein at the cell membrane due to its blockade by the endoplasmic reticulum (ER) quality control. Moreover, we demonstrated that inhibition of the ER α‐mannosidase I activity using kifunensine could rescue the mutant protein localization at the cell membrane. Here, we investigate 25 addi... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5415621 Wed, 16 Nov 2011 05:00:00 +0100 5415621 http://www.medworm.com/index.php?rid=5548754&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21656 AbstractMany nonsynonymous single nucleotide polymorphisms (nsSNPs) are disease causing due to effects at protein‐protein interfaces. We have integrated a database of the three‐dimensional (3D) structures of human protein/protein complexes and the humsavar database of nsSNPs. We analyzed the location of nsSNPS in terms of their location in the protein core, at protein‐protein interfaces, and on the surface when not at an interface. Disease‐causing nsSNPs that do not occur in the protein core are preferentially located at protein‐protein interfaces rather than surface noninterface regions when compared to random segregation. The disruption of the protein‐protein interaction can be explained by a range of structural effects including the loss of an electrostatic salt bridge, the ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5548754 Wed, 09 Nov 2011 05:00:00 +0100 5548754 http://www.medworm.com/index.php?rid=5531297&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21654 We describe some limitations of in silico analyses of NGS data that emphasize the need for experimental confirmation. Using NGS, we recently identified an apparently homozygous missense mutation in NUBPL in a patient with mitochondrial complex I deficiency. Causality was established via lentiviral correction studies with wild‐type NUBPL cDNA. NGS data, however, provided an incomplete understanding of the genetic abnormality. We show that the maternal allele carries an unbalanced inversion, while the paternal allele carries a branch‐site mutation in addition to the missense mutation. We demonstrate that the branch‐site mutation, which is present in approximately one of 120 control chromosomes, likely contributes to pathogenicity and may be one of the most common autosomal mutations ca... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5531297 Wed, 09 Nov 2011 05:00:00 +0100 5531297 http://www.medworm.com/index.php?rid=5394514&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21656 AbstractMany non‐synonymous single nucleotide polymorphisms (nsSNPs) are disease causing due to effects at protein‐protein interfaces. We have integrated a database of the 3D structures of human protein/protein complexes and the humsavar database of nsSNPs. We analysed the location of nsSNPS in terms of their location in the protein core, at protein‐protein interfaces and on the surface when not at an interface. Disease‐causing nsSNPs that do not occur in the protein core are preferentially located at protein‐protein interfaces rather than surface non‐interface regions when compared to random segregation. The disruption of the protein/protein interaction can be explained by a range of structural effects including the loss of an electrostatic salt bridge, the destabilisation due... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394514 Wed, 09 Nov 2011 05:00:00 +0100 5394514 http://www.medworm.com/index.php?rid=5394513&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21655 AbstractMutations in the SLC4A11 gene, which encodes a plasma membrane borate transporter, cause recessive congenital hereditary endothelial corneal dystrophy type 2 (CHED2), corneal dystrophy and perceptive deafness (Harboyan syndrome) and dominant late‐onset Fuchs endothelial corneal dystrophy (FECD). We analyzed missense SLC4A11 mutations identified in FECD and CHED2 patients and expressed in transfected HEK 293 cells. Chemical cross‐linking and migration in non‐denaturing gels showed that SLC4A11 exists as a dimer. Furthermore, co‐immunoprecipitation of epitope‐tagged proteins reveled heteromeric interactions between wild type (WT) and mutant SLC4A11 proteins. When expressed alone, FECD and CHED2‐causing mutant SLC4A11 proteins are primarily retained intracellularly. Co‐e... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394513 Wed, 09 Nov 2011 05:00:00 +0100 5394513 http://www.medworm.com/index.php?rid=5491462&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21652 AbstractAdiponectin is most abundantly expressed in adipose tissue and well known to play an important role in metabolic regulation. Several studies have attempted to identify the genetic determinants of metabolic syndrome (MetS), though no study has revealed a cis‐ or trans‐single nucleotide polymorphism (SNP) that affects plasma adiponectin levels, except the adiponectin structure gene and genes encoding adiponectin‐regulatory proteins. We performed a genome‐wide association study in regards to plasma adiponectin concentrations in 3,310 Japanese subjects. We identified the strongest statistically associated SNP (rs4783244) with adiponectin levels (P = 3.8 × 10−19) in the first intron of CDH13 (T‐cadherin) gene in a 30‐kb haplotype block covering the promoter region to firs... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5491462 Mon, 07 Nov 2011 05:00:00 +0100 5491462 http://www.medworm.com/index.php?rid=5394517&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21652 AbstractAdiponectin is most abundantly expressed in adipose tissue and well known to play an important role in metabolic regulation. Several studies have attempted to identify the genetic determinants of metabolic syndrome, though no study has revealed a cis‐ or trans‐single nucleotide polymorphism (SNP) that affects plasma adiponectin levels, except the adiponectin structure gene and genes encoding adiponectin‐regulatory proteins. We performed a genome‐wide association study in regards to plasma adiponectin concentrations in 3310 Japanese subjects. We identified the strongest statistically associated SNP (rs4783244) with adiponectin levels (p=3.8 × 10‐19) in the first intron of CDH13 (T‐cadherin) gene in a 30 kb‐haplotype block covering the promoter region to first intron. ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394517 Mon, 07 Nov 2011 05:00:00 +0100 5394517 http://www.medworm.com/index.php?rid=5394516&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21650 We report on a consanguineous family with autosmoal recessive inheritance and clinical characteristics of Ataxia with Oculomotor Apraxia type 2, and no mutations in the SETX gene. We mapped the Ataxia with Oculomotor Apraxia locus in this family to chromosome 17p12‐p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394516 Mon, 07 Nov 2011 05:00:00 +0100 5394516 http://www.medworm.com/index.php?rid=5394515&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21653 AbstractMutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from Leber Congenital Amaurosis (LCA) to rod‐cone dystrophy (also called retinitis pigmentosa (RP)). Moreover, retinal dystrophies resulting from CRB1 mutations may be accompanied by specific fundus features: preservation of the para‐arteriolar retinal pigment epithelium (PPRPE) and retinal telangiectasia with exudation (also referred to as Coats‐like vasculopathy). In this publication we report seven novel mutations and classify over 150 reported CRB1 sequence variants that were found in more that 240 patients. The data from previous reports was used to analyse a potential correlation between CRB1 variants and the clinical features of respective patients. This meta‐ana... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394515 Mon, 07 Nov 2011 05:00:00 +0100 5394515 http://www.medworm.com/index.php?rid=5394518&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21651 AbstractDystrophic Epidermolysis Bullosa (DEB) is a genetic disease caused by mutations in the COL7A1 gene that is inherited in the autosomal dominant or recessive mode. We have developed a curated, freely accessible COL7A1 ‐ specific database (www.col7.info), which contains more than 730 reported and unpublished sequence variants of the gene. Molecular defects are reported according to HGVS recommendation. The clinical description module is provided with an advanced search tool together with a CSV‐ data format download option. This compilation of COL7A1 data and nomenclature is aimed at assisting molecular and clinical geneticists to enhance the collaboration between researchers worldwide. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394518 Fri, 04 Nov 2011 04:00:00 +0100 5394518 http://www.medworm.com/index.php?rid=5491463&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21648 In this study, we identified a novel, heterozygous c.385G<T mutation in CRYGC that resulted in the substitution of a highly conserved glycine by cysteine at codon 129 (p.Gly129Cys) in a three‐generation Chinese family with autosomal dominant congenital nuclear cataract by sequencing candidate genes. Using zebrafish as a model, we demonstrated that γC‐crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H‐bonding network in the C‐terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC‐crystallin, and a significant incre... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5491463 Thu, 03 Nov 2011 04:00:00 +0100 5491463 http://www.medworm.com/index.php?rid=5372209&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21645 AbstractAutozygosity mapping has been a powerful method for the identification of autosomal recessive disease genes. However, the approach is limited by the availability of suitable consanguineous pedigrees. While rare autosomal recessive diseases are over‐represented in consanguineous families, a significant proportion of affected patients nonetheless originate in families where the parents are apparently unrelated. However, due to their relative rarity and the heterogeneity of disease alleles, it has proved difficult to use these patients to identify disease loci. Therefore, we developed “Phaser”, a computer application which is able to infer the phase of SNP alleles and so haplotype entire chromosomes in small nuclear families (http://dna.leeds.ac.uk/Phaser). Once the index case's... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372209 Thu, 03 Nov 2011 04:00:00 +0100 5372209 http://www.medworm.com/index.php?rid=5372208&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21646 AbstractInformation about genetic variation has been collected for some twenty years into registries, known as locus specific databases (LSDBs), which nowadays often contain information in addition to the actual genetic variation. Several issues have to be taken into account when considering establishing and maintaining LSDBs and these have been discussed previously in a number of articles describing guidelines and recommendations. This information is widely scattered and, for a newcomer, it would be difficult to obtain the latest information and guidance. Here, a sequence of steps essential for establishing an LSDB is discussed together with guidelines for each step. Curators need to collect information from various sources, code it in systematic way and distribute to the research and cli... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372208 Thu, 03 Nov 2011 04:00:00 +0100 5372208 http://www.medworm.com/index.php?rid=5372207&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21647 AbstractHerein we have studied a consanguineous Egyptian family with two children diagnosed with severe autosomal recessive osteogenesis imperfecta (AR‐OI) and a large umbilical hernia. Homozygosity mapping in this family showed lack of linkage to any of the previously known AR‐OI genes, but revealed a 10.27 MB homozygous region on chromosome 8p in the two affected sibs, which comprised the procollagen I C‐propeptide (PICP) endopeptidase gene BMP1. Mutation analysis identified both patients with a Phe249Leu homozygous missense change within the BMP1 protease domain involving a residue which is conserved in all members of the astacin group of metalloproteases. Type I procollagen analysis in supernatants from cultured fibroblasts demonstrated abnormal PICP processing in patient‐deriv... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372207 Thu, 03 Nov 2011 04:00:00 +0100 5372207 http://www.medworm.com/index.php?rid=5463705&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21640 AbstractRod–cone dystrophies (retinitis pigmentosa [RP]) are a clinically and genetically heterogeneous group of inherited retinal disorders characterized by photoreceptor degeneration. RP1 is a major gene underlying autosomal dominant (ad) RP, though prevalence figures vary depending on the origin of the cases from 0–10% of all adRP. Some mutations in RP1 also lead to autosomal recessive (ar) RP. Herein, we review all previously reported and several novel RP1 mutations in relation to the associated phenotype in RP1 patients from a French adRP cohort. Prevalence studies from this cohort show that 5.3% of the cases have RP1 mutations. This is in accordance with other studies reported from United Kingdom and United States. The majority of mutations represent truncating mutations that are... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5463705 Wed, 02 Nov 2011 04:00:00 +0100 5463705 http://www.medworm.com/index.php?rid=5372210&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21640 AbstractRod‐cone dystrophies (RP) are a clinically and genetically heterogeneous group of inherited retinal disorders characterized by photoreceptor degeneration. RP1 is a major gene underlying autosomal dominant (ad) RP though prevalence figures vary depending on the origin of the cases from 0%‐10% of all adRP. Some mutations in RP1 also lead to autosomal recessive RP. Herein we review all previously reported and several novel RP1 mutations in relation to the associated phenotype in patients from a French adRP cohort. Prevalence studies from this cohort show that 5.3% of the cases have RP1 mutations. This is in accordance with other studies reported from UK and USA. The majority of mutations represent truncating mutations which are located in a hot spot region of the gene. Similarly, ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372210 Wed, 02 Nov 2011 04:00:00 +0100 5372210 http://www.medworm.com/index.php?rid=5446416&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21639 In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS. Hum Mutat 00:1–9, 2011. © 2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5446416 Tue, 01 Nov 2011 04:00:00 +0100 5446416 http://www.medworm.com/index.php?rid=5394512&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21654 We describe some limitations of in silico analyses of NGS data that emphasise the need for experimental confirmation. Using NGS, we recently identified an apparently homozygous missense mutation in NUBPL in a patient with mitochondrial complex I deficiency. Causality was established via lentiviral correction studies with wild‐type NUBPL cDNA. NGS data, however, provided an incomplete understanding of the genetic abnormality. We show that the maternal allele carries an unbalanced inversion, while the paternal allele carries a branch site mutation in addition to the missense mutation. We demonstrate that the branch site mutation, which is present in ∼1/120 control chromosomes, likely contributes to pathogenicity and may be one of the most common autosomal mutations causing mitochondrial ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394512 Tue, 01 Nov 2011 04:00:00 +0100 5394512 http://www.medworm.com/index.php?rid=5372216&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21636 This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372216 Tue, 01 Nov 2011 04:00:00 +0100 5372216 http://www.medworm.com/index.php?rid=5372215&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21643 This study demonstrates that rare non‐synonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to NTDs. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372215 Tue, 01 Nov 2011 04:00:00 +0100 5372215 http://www.medworm.com/index.php?rid=5372214&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21644 AbstractNonallelic homologous recombination (NAHR) is the major mechanism underlying recurrent genomic rearrangements, including the large deletions at 17q11.2 that cause neurofibromatosis type 1 (NF1). Here we identify a novel NAHR hotspot, responsible for type‐3 NF1 deletions which span 1.0‐Mb. Breakpoint clustering within this 1‐kb hotspot, termed PRS3, was noted in 10 of 11 known type‐3 NF1 deletions. PRS3 is located within the LRRC37B pseudogene of the NF1‐REPb and NF1‐REPc low‐copy repeats. In contrast to other previously characterized NAHR hotspots, PRS3 has not developed on a pre‐existing allelic homologous recombination hotspot. Furthermore, the variation pattern of PRS3 and its flanking regions are unusual since only NF1‐REPc (and not NF1‐REPb) is characterize... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372214 Tue, 01 Nov 2011 04:00:00 +0100 5372214 http://www.medworm.com/index.php?rid=5372213&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21639 In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372213 Tue, 01 Nov 2011 04:00:00 +0100 5372213 http://www.medworm.com/index.php?rid=5372212&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21641 AbstractMiRNAs are studied as key regulators of gene expression involved in different diseases. Several single nucleotide polymorphisms (SNPs) in miRNA genes or target sites (miRNA‐related SNPs) have been proved to be associated with human diseases by affecting the miRNA mediated regulatory function. To systematically analyze miRNA‐related SNPs and their effects, we performed a genome‐wide scan for SNPs in human pre‐miRNAs, miRNA flanking regions, target sites and designed a pipeline to predict the effects of them on miRNA‐target interaction. As a result, we identified 48 SNPs in human miRNA seed regions and thousands of SNPs in 3'‐ untranslated regions with the potential to either disturb or create miRNA‐target interactions. Furthermore, we experimentally confirmed 7 loss‐... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372212 Tue, 01 Nov 2011 04:00:00 +0100 5372212 http://www.medworm.com/index.php?rid=5372211&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21642 AbstractVariations are mostly due to non‐synonymous single nucleotide polymorphisms (nsSNPs) some of which are associated with certain diseases. Phenotypic effects of a large number of nsSNPs have not been characterized. Although several methods have been developed to predict the effects of nsSNPs as “disease” or “neutral” there is still a need for development of methods with improved prediction accuracies. We, therefore, developed a SVM‐based method named Hansa which uses a novel set of discriminatory features to classify nsSNPs into disease (pathogenic) and benign (neutral) types. Validation studies on a benchmark dataset and further on an independent dataset of well characterized known disease and neutral mutations show that Hansa outperforms the other known methods. For exa... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372211 Tue, 01 Nov 2011 04:00:00 +0100 5372211 http://www.medworm.com/index.php?rid=5372206&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21648 In this study, we identified a novel, heterozygous c.385G>T mutation in CRYGC that resulted in the substitution of a highly conserved glycine by cysteine at codon 129 (p.Gly129Cys) in a three‐generation Chinese family with autosomal dominant congenital nuclear cataract by sequencing candidate genes. Using zebrafish as a model, we demonstrated that γC‐crystallin p.Gly129Cys mutant caused the vacuole and the incomplete denucleation of lens, recapitulating the cataract phenotype in human beings. Molecular modeling and spectroscopic studies indicated that the mutation impaired the tertiary structure of the protein by modifying the H‐bonding network in the C‐terminal domain. The mutation led to a dramatic decrease in the thermal stability of γC‐crystallin, and a significant incre... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372206 Tue, 01 Nov 2011 04:00:00 +0100 5372206 http://www.medworm.com/index.php?rid=5329116&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21578 AbstractLecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high‐density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL‐cholesterol (HDL‐c) deficiency while heterozygotes have half normal HDL‐c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL‐c to better understand the molecular basis of low HDL‐c in our patients. LCAT was sequenced in 98 patients referred for HDL‐c <5th percentile and in four patients referred for low HDL‐c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329116 Wed, 19 Oct 2011 13:14:37 +0100 5329116 http://www.medworm.com/index.php?rid=5329115&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21620 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329115 Wed, 19 Oct 2011 13:14:21 +0100 5329115 http://www.medworm.com/index.php?rid=5329114&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21619 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329114 Wed, 19 Oct 2011 13:14:20 +0100 5329114 http://www.medworm.com/index.php?rid=5329113&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21618 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329113 Wed, 19 Oct 2011 13:14:19 +0100 5329113 http://www.medworm.com/index.php?rid=5329108&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21635 AbstractCharcot‐Marie‐Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl‐tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl‐tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329108 Wed, 19 Oct 2011 13:13:19 +0100 5329108 http://www.medworm.com/index.php?rid=5394519&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21635 AbstractCharcot‐Marie‐Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl‐tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl‐tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5394519 Tue, 18 Oct 2011 04:00:00 +0100 5394519 http://www.medworm.com/index.php?rid=5329110&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21633 AbstractMutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas. To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; non‐truncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability and the mutations in these tumors were ou... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329110 Tue, 18 Oct 2011 04:00:00 +0100 5329110 http://www.medworm.com/index.php?rid=5329109&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21634 AbstractUSH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the 2 affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome with a mutation causing activation of a pseudoexon. The finding of this alteration in eight other individuals of mixed European origin, emphasises the importance of including RNA analysis in a comprehensive diagnostic service. Finally, ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329109 Tue, 18 Oct 2011 04:00:00 +0100 5329109 http://www.medworm.com/index.php?rid=5329112&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21632 AbstractA recent challenge for investigators studying the progressive neurological disease ataxia‐telangiectasia (A‐T) is to identify mutations whose effects might be alleviated by mutation‐targeted therapies. We studied ATM mutations in eight families of Japanese A‐T patients (JPAT) and were able to identify all 16 mutations. The probands were compound heterozygotes in seven families, and one (JPAT2) was homozygous for a frameshift mutation. All mutations ‐ four frameshift, two nonsense, four large genomic deletions, and six affecting splicing ‐ were novel except for c.748C>T found in family JPAT6 and c.2639‐384A>G found in family JPAT11/12. Using an established lymphoblastoid cell line (LCL) of patient JPAT11, ATM protein was restored to levels approaching wildtype by... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329112 Mon, 17 Oct 2011 04:00:00 +0100 5329112 http://www.medworm.com/index.php?rid=5329111&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21631 AbstractPseudoachondroplasia (PSACH) results from mutations in cartilage oligomeric matrix protein (COMP) and the p.D469del mutation within the type III repeats of COMP accounts for ∼30% of PSACH. To determine disease mechanisms of PSACH in vivo, we introduced the Comp D469del mutation into the mouse genome. Mutant animals were normal at birth but grew slower than their wild‐type littermates and developed short‐limb dwarfism. In the growth plates of mutant mice chondrocyte columns were reduced in number and poorly organized, whilst mutant COMP was retained within the ER of cells. Chondrocyte proliferation was reduced and apoptosis was both increased and spatially dysregulated. Previous studies on COMP mutations have shown mutant COMP is co‐localized with chaperone proteins and we h... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5329111 Mon, 17 Oct 2011 04:00:00 +0100 5329111 http://www.medworm.com/index.php?rid=5372218&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21628 AbstractAs genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an “unclassified” variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org)... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372218 Tue, 11 Oct 2011 04:00:00 +0100 5372218 http://www.medworm.com/index.php?rid=5372217&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21627 We describe the components of the model and explain how these can be combined to calculate a posterior probability of pathogenicity for each VUS. We explain how the model can be applied to public data and provide tables that list the VUS that have been classified as not pathogenic or pathogenic using this method. While we use BRCA1 and BRCA2 VUS as examples, the method can be used as a framework for classification of the pathogenicity of VUS in other cancer genes. Hum Mutat 00:1–14, 2011. © 2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372217 Tue, 11 Oct 2011 04:00:00 +0100 5372217 http://www.medworm.com/index.php?rid=5309525&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21629 AbstractUnclassified sequence variants (UV) arising from clinical mutation screening of cancer susceptibility genes present a frustrating issue to clinical genetics services and the patients that they serve. We created an open‐access database holding missense substitutions from the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. The main inclusion criterion is that each variant should have been assessed in a published work that used the Bayesian integrated evaluation of unclassified BRCA gene variants. Transfer of data on these substitutions from the original publications to our database afforded an opportunity to analyze the missense substitutions under a single model and to remove inconsistencies that arose during the evolution of the integrated evaluation over the last... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309525 Tue, 11 Oct 2011 04:00:00 +0100 5309525 http://www.medworm.com/index.php?rid=5309524&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21628 AbstractAs genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests result in the detection of a genetic variant for which disease association is not known. The finding of an ‘unclassified’ variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309524 Tue, 11 Oct 2011 04:00:00 +0100 5309524 http://www.medworm.com/index.php?rid=5309523&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21626 We describe the tasks involved, the steps to take and the issues that might occur. Our overview is a first step towards establishing overall guidelines for database curation and ultimately covers one aspect of establishing quality‐assured gene variant databases. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309523 Tue, 11 Oct 2011 04:00:00 +0100 5309523 http://www.medworm.com/index.php?rid=5309522&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21625 AbstractThere is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementation of RAD51C into routine clinical genetic testing. Consequently, we have performed a large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer. Our data confirms a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309522 Tue, 11 Oct 2011 04:00:00 +0100 5309522 http://www.medworm.com/index.php?rid=5309521&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21624 AbstractThe neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative disorders. Most are autosomal recessively inherited. Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss and premature death. Mutations in eight genes (PPT1/CLN1, TPP1/CLN2, CLN3, CLN5, CLN6, MFSD8/CLN7, CLN8) have been identified and several more are predicted to exist, including two provisionally named CLN4 and CLN9. Despite excessive in vitro and in vivo studies the precise functions of the NCL proteins and the disease mechanisms remain elusive. To date 364 NCL‐causing mutations are known, with 90 novel disease‐causing mutations reported here. These are reviewed with an emphasis on their complex correlation to phenotypes. Dif... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309521 Tue, 11 Oct 2011 04:00:00 +0100 5309521 http://www.medworm.com/index.php?rid=5309520&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21623 We present 6 additional probands with RCDP2 and 3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309520 Tue, 11 Oct 2011 04:00:00 +0100 5309520 http://www.medworm.com/index.php?rid=5309519&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21622 AbstractThe Serotonin receptor 1A (encoded by the HTR1A gene) plays a critical role in serotonergic transmission and was linked with many human diseases. A 33‐year‐old woman with rare menstrual cycle‐dependent fever showed abnormal estrogen profile and responded well to the HTR1A agonist buspirone, suggesting that her fevers were allied to estrogen‐related HTR1A deficiency. We identified an adenine deletion 480‐bases upstream of the translation start site (i.e., ‐480delA) of HTR1A in this patient. To determine the underlying mechanism of ‐480delA‐mediated HTR1A deficiency, we first showed that HTR1A ‐480‐region can be bound by multiple nuclear protein(s). We then identified poly (ADP‐ribose) polymerase (PARP1) as one of the proteins that binds to HTR1A ‐480‐region... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309519 Tue, 11 Oct 2011 04:00:00 +0100 5309519 http://www.medworm.com/index.php?rid=5309518&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21621 This study confirms the importance of the FAM20A protein in enamel biomineralization as well as tooth eruption. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309518 Tue, 11 Oct 2011 04:00:00 +0100 5309518 http://www.medworm.com/index.php?rid=5309517&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21630 AbstractFamilial hypercholesterolemia (FH) is an autosomal dominant disorder mostly caused by mutations in the LDLR gene. Although the detection of functional mutations in the LDLR gene provides an unequivocal diagnosis of the FH condition, there are many variants whose pathogenicity is still unknown. The aims of this study were to set up a rapid method to determine the effect of LDLR mutations, thereby providing an accurate diagnosis of FH, and to functionally characterize six LDLR mutations detected at high frequency by the LIPOchip® platform in the Spanish population. LDLR expression and activity were analyzed by one‐single‐step flow cytometry assay and confocal microscopy. Splicing effects were determined by sequencing RT‐PCR products. The analysis of three heterozygous variants... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309517 Tue, 11 Oct 2011 04:00:00 +0100 5309517 http://www.medworm.com/index.php?rid=5309516&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21627 We describe the components of the model and explain how these can be combined to calculate a posterior probability of pathogenicity for each VUS. We explain how the model can be applied to public data and provide Tables that list the VUS that have been classified as not pathogenic or pathogenic using this method. While we use BRCA1 and BRCA2 VUS as examples, the method can be used as a framework for classification of the pathogenicity of VUS in other cancer genes. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309516 Sat, 01 Oct 2011 04:00:00 +0100 5309516 http://www.medworm.com/index.php?rid=5280086&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21586 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5280086 Fri, 30 Sep 2011 04:00:00 +0100 5280086 http://www.medworm.com/index.php?rid=5256164&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21616 AbstractRecently the genome sequences from several cancers have been published, along with the genome from a non‐cancer tissue from the same individual, allowing the identification of new somatic mutations in the cancer. We show that there is significant variation in the density of mutations at the 1MB scale within three cancer genomes and that the density of mutations is correlated between them. We also show that the density of mutations is correlated to that in the germ‐line, as measured by the divergence between humans and chimpanzees and humans and macaques. We show that the density of mutations is correlated to GC content, replication time, distance to telomere and centromere, gene density and nucleosome occupancy in the cancer genomes. However, overall, all factors explain less t... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5256164 Mon, 26 Sep 2011 19:21:46 +0100 5256164 http://www.medworm.com/index.php?rid=5342144&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21616 AbstractRecently, the genome sequences from several cancers have been published, along with the genome from a noncancer tissue from the same individual, allowing the identification of new somatic mutations in the cancer. We show that there is significant variation in the density of mutations at the 1‐Mb scale within three cancer genomes and that the density of mutations is correlated between them. We also demonstrate that the density of mutations is correlated to that in the germline, as measured by the divergence between humans and chimpanzees and humans and macaques. We show that the density of mutations is correlated to the guanine and cytosine (GC) conent, replication time, distance to telomere and centromere, gene density, and nucleosome occupancy in the cancer genomes. However, ove... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5342144 Fri, 23 Sep 2011 04:00:00 +0100 5342144 http://www.medworm.com/index.php?rid=5244763&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21617 In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome‐suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5244763 Fri, 23 Sep 2011 03:39:23 +0100 5244763 http://www.medworm.com/index.php?rid=5244765&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21615 AbstractDisruption of the long‐range cis‐regulation of developmental gene expression is increasingly recognized as a cause of human disease. Here, we report a novel type of long‐range cis‐regulatory mutation, in which ectopic expression of a gene is driven by an enhancer that is not its own. We have termed this gain of regulatory information as ‘enhancer adoption’. We mapped the breakpoints of a de novo 7q inversion in a child with features of a holoprosencephaly spectrum (HPES) disorder and severe upper limb syndactyly with lower limb synpolydactyly. The HPES plausibly results from the 7q36.3 breakpoint dislocating the sonic hedgehog (SHH) gene from enhancers that are known to drive expression in the early forebrain. However, the limb phenotype cannot be explained by loss of k... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5244765 Wed, 21 Sep 2011 04:00:00 +0100 5244765 http://www.medworm.com/index.php?rid=5244764&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21614 We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3‐Mb to 12‐Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that NAHR caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy‐number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay or intellectual disability as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5244764 Wed, 21 Sep 2011 04:00:00 +0100 5244764 http://www.medworm.com/index.php?rid=5244767&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21576 AbstractMutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin‐1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin‐1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in‐frame deletion mutations with mil... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5244767 Tue, 20 Sep 2011 04:00:00 +0100 5244767 http://www.medworm.com/index.php?rid=5244766&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21595 In this study we constructed dbHCCvar, a free online database of human genetic variations in HCC. Eligible publications were collected from PubMed, and detailed information and major research data from each eligible study were then extracted and recorded in our database. As a result, dbHCCvar contains almost all human genetic variations reported to be associated or not associated with HCC risk, clinical pathology, drug reaction, survival, or recurrence to date. It is expected that dbHCCvar will function as a useful tool for researchers to facilitate the search and identification of new genetic markers for HCC. dbHCCvar is free for all visitors at http://GenetMed.fudan.edu.cn/dbHCCvar. ©2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5244766 Tue, 20 Sep 2011 04:00:00 +0100 5244766 http://www.medworm.com/index.php?rid=5231329&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21554 We examined the molecular pathomechanism of a BFNS‐causing mutation (p.N258S) in the extracellular S5‐H5 loop of KV7.2. Wild type (WT) and mutant channels, expressed in both Xenopus laevis oocytes and CHO cells, were studied using electrophysiological techniques. The results revealed a pronounced loss‐of‐function with a dominant‐negative effect of the mutant on WT KV7.2 and KV7.3 channels. Since single‐channel recordings of KV7.3–KV7.2 and KV7.3–N285S concatemers showed similar properties for both constructs, we hypothesized that the observed reduction in current amplitude was due to a folding and trafficking defect, which was confirmed by biochemical and immunocytochemical experiments revealing a reduced number of mutant channels in the surface membrane. Furthermore, rescu... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231329 Mon, 19 Sep 2011 16:46:01 +0100 5231329 http://www.medworm.com/index.php?rid=5231328&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21545 AbstractCystic fibrosis (CF) is characterized as a single‐gene disorder with a simple, autosomal recessive mode of inheritance. However, translation of cystic fibrosis transmembrane conductance regulator (CFTR) genotype into CF phenotype is influenced by nucleotide sequence variations at multiple genetic loci, and individuals heterozygous for CFTR mutations are predisposed to a range of CFTR‐related conditions, such as disseminated bronchiectasis. CF disease severity and CFTR‐related conditions are more akin to complex, multifactorial traits, which are increasingly being associated with mutations that perturb gene expression. We have identified a patient with disseminated bronchiectasis, who is heterozygous for a single‐nucleotide substitution in the CFTR 5′ untranslated region (... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231328 Mon, 19 Sep 2011 16:46:00 +0100 5231328 http://www.medworm.com/index.php?rid=5231327&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21594 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231327 Mon, 19 Sep 2011 16:45:57 +0100 5231327 http://www.medworm.com/index.php?rid=5231326&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21593 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231326 Mon, 19 Sep 2011 16:45:40 +0100 5231326 http://www.medworm.com/index.php?rid=5231325&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21592 (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231325 Mon, 19 Sep 2011 16:45:38 +0100 5231325 http://www.medworm.com/index.php?rid=5231315&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21612 AbstractImplementation of multiplex ligation‐dependent probe amplification (MLPA) for thalassemia causing deletions has lead to the detection of new rearrangements. Knowledge of the exact breakpoint sequences should give more insight in the molecular mechanisms underlying these rearrangements, and would facilitate the design of gap‐PCRs. We have designed a custom fine‐tiling array with oligonucleotides covering the complete globin gene clusters. We hybridized 27 DNA samples containing newly identified deletions and 9 positive controls. We designed specific primers to amplify relatively short fragments containing the breakpoint sequence and analyzed these by direct sequencing. Results from 9 positive controls showed that arrayCGH is suitable to detect small and large rearrangements. W... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231315 Mon, 19 Sep 2011 16:44:35 +0100 5231315 http://www.medworm.com/index.php?rid=5372221&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21610 AbstractBicaudal C homologue 1 (Bicc1) knockout in mice causes polycystic kidney disease and pancreas development defects, including a reduction in insulin‐producing β‐cells and ensuing diabetes. We therefore screened 137 patients with renal abnormalities or association of early‐onset diabetes and renal disease for genetic alterations in BICC1. We identified two heterozygous mutations, one nonsense in the first K Homology (KH) domain and one missense in the sterile alpha motif (SAM) domain. In mice, Bicc1 blocks canonical Wnt signaling, mostly via its SAM domain. We show that the human BICC1, similar to its mouse counterpart, blocks canonical Wnt signaling. The nonsense mutation identified results in a complete loss of Wnt inhibitory activity. The point mutation in the SAM domain ha... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372221 Thu, 15 Sep 2011 04:00:00 +0100 5372221 http://www.medworm.com/index.php?rid=5372220&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21611 In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED. Hum Mutat 00:1–14, 2011. © 2011 Wiley Periodicals, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372220 Thu, 15 Sep 2011 04:00:00 +0100 5372220 http://www.medworm.com/index.php?rid=5372219&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21612 AbstractImplementation of multiplex ligation‐dependent probe amplification (MLPA) for thalassemia causing deletions has lead to the detection of new rearrangements. Knowledge of the exact breakpoint sequences should give more insight into the molecular mechanisms underlying these rearrangements, and would facilitate the design of gap‐PCRs. We have designed a custom fine‐tiling array with oligonucleotides covering the complete globin gene clusters. We hybridized 27 DNA samples containing newly identified deletions and nine positive controls. We designed specific primers to amplify relatively short fragments containing the breakpoint sequence and analyzed these by direct sequencing. Results from nine positive controls showed that array comparative genomic hybridization (aCGH) is suitab... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5372219 Thu, 15 Sep 2011 04:00:00 +0100 5372219 http://www.medworm.com/index.php?rid=5309526&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21607 AbstractPrimary carnitine deficiency is caused by defective OCTN2 carnitine transporters encoded by the SLC22A5 gene. Lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy. Recently, asymptomatic mothers with primary carnitine deficiency were identified by low carnitine levels in their infant by newborn screening. Here, we evaluate mutations in the SLC22A5 gene and carnitine transport in fibroblasts from symptomatic patients and asymptomatic women. Carnitine transport was significantly reduced in fibroblasts obtained from all patients with primary carnitine deficiency, but was significantly higher in the asymptomatic women's than in the symptomatic patients' fibroblasts (P < 0.01). By contrast, ergothi... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5309526 Thu, 15 Sep 2011 04:00:00 +0100 5309526 http://www.medworm.com/index.php?rid=5231321&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21607 AbstractPrimary carnitine deficiency is caused by defective OCTN2 carnitine transporters encoded by the SLC22A5 gene. Lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy. Recently, asymptomatic mothers with primary carnitine deficiency were identified by low carnitine levels in their infant by newborn screening. Here we evaluate mutations in the SLC22A5 gene and carnitine transport in fibroblasts from symptomatic patients and asymptomatic women. Carnitine transport was significantly reduced in fibroblasts obtained from all patients with primary carnitine deficiency, but was significantly higher in the asymptomatic women's than in the symptomatic patients' fibroblasts (p < 0.01). By contrast, ergothio... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231321 Thu, 15 Sep 2011 04:00:00 +0100 5231321 http://www.medworm.com/index.php?rid=5231320&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21608 AbstractA large number of missense mutations have been identified within the tumor suppressor gene BRCA1. Most of them, called “variants of unknown significance” (VUS), cannot be classified as pathogenic or neutral by genetic methods, which complicates their cancer risk assessment. Functional assays have been developed to circumvent this uncertainty. They aim to determine how VUS impact the BRCA1 protein structure or function, thereby giving an indication of their potential to cause cancer. So far, three relevant assays have been designed in yeast and used on large sets of variants. However, they are limited to variants mapped in restricted domains of BRCA1. One of them, the small colony phenotype (SCP) assay, monitors the BRCA1‐dependent growth of yeast colonies that increases with ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231320 Thu, 15 Sep 2011 04:00:00 +0100 5231320 http://www.medworm.com/index.php?rid=5231319&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21609 AbstractSplicing is the most frequently altered biological process by mutations within gene regions. Information for splicing is recognized by several factors that bind pre‐mRNA sequence and, through coordinated interaction, yield mature transcripts. Some in silico methods have been developed to predict if a mutation leads to aberrant splicing patterns. We previously created SpliceAid tool that is able to minimize false positive predictions because it adopts strictly experimental RNA target motifs bound by splicing proteins in humans. In order to improve prediction accuracy and better understand the splicing outcome, the tissue specificity of each splicing regulatory factor has to be taken into account. Here, we have developed SpliceAid 2 by adding the expression data related to the spli... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231319 Thu, 15 Sep 2011 04:00:00 +0100 5231319 http://www.medworm.com/index.php?rid=5231318&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21610 AbstractBicaudal C homologue 1 (Bicc1) knock‐out in mice causes polycystic kidney disease and pancreas development defects, including a reduction in insulin‐producing β‐cells and ensuing diabetes. We therefore screened 137 patients with renal abnormalities or association of early‐onset diabetes and renal disease for genetic alterations in BICC1. We identified two heterozygous mutations, one nonsense in the first KH domain and one missense in the SAM domain. In mice, Bicc1 blocks canonical Wnt signalling, mostly via its SAM domain. We show that the human BICC1, similar to its mouse counterpart, blocks canonical Wnt signaling. The nonsense mutation identified results in a complete loss of Wnt inhibitory activity. The point mutation in the SAM domain has a similar effect to a complet... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231318 Thu, 15 Sep 2011 04:00:00 +0100 5231318 http://www.medworm.com/index.php?rid=5231317&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21611 In this study we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231317 Thu, 15 Sep 2011 04:00:00 +0100 5231317 http://www.medworm.com/index.php?rid=5231316&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21613 This study suggests that CPA6 is genetically linked to an autosomal recessive familial form of FS and TLE and is associated with sporadic TLE cases. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231316 Thu, 15 Sep 2011 04:00:00 +0100 5231316 http://www.medworm.com/index.php?rid=5231322&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21606 AbstractSOX2 is an early developmental transcription factor and marker of stem cells that has recently been implicated in the development of the pituitary gland. Heterozygous SOX2 mutations have been described in patients with hypopituitarism and severe ocular abnormalities. In the majority of published cases the pituitary gland is either small or normal in size. Here we report two unrelated patients with SOX2 haploinsufficiency (a heterozygous gene deletion and a novel p.F48X mutation) who developed non‐progressive pituitary tumours of early onset, suggesting a congenital etiology. The truncating mutation resulted in significant loss of function and impaired nuclear localisation of the mutant protein, in addition to a failure to repress β‐catenin transcriptional activity in vitro. Th... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5231322 Wed, 14 Sep 2011 04:00:00 +0100 5231322 http://www.medworm.com/index.php?rid=5216637&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21556 AbstractWith the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus‐specific databases (LSDBs) curate one or more specific genes' mutation data along with high‐quality phenotypes. Although some genotype‐phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related pheno... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5216637 Mon, 12 Sep 2011 04:00:00 +0100 5216637 http://www.medworm.com/index.php?rid=5202223&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21597 AbstractWith the advent of cheap rapid methods for whole‐genome SNP genotyping and the completion of the Human Genome Project, mapping disease loci has become primarily a bioinformatic rather than a laboratory problem. Here, we describe DominantMapper, a computer program that implements a rule‐based analysis algorithm for the detection of dominant disease loci in either a small number of nuclear families or a single large nuclear family. To demonstrate its utility, we present the successful analysis of two pedigrees in which the affected individuals carry either APC or TSPAN12 mutations. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202223 Thu, 08 Sep 2011 04:00:00 +0100 5202223 http://www.medworm.com/index.php?rid=5202222&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21591 AbstractChoroideremia (CHM), an X‐linked degeneration of the retinal pigmented epithelium (RPE), photoreceptors, and choroid, ultimately leads to blindness. It is caused by loss‐of‐function of the CHM gene product, the Rab escort protein 1 (REP1) that is involved, together with its homologue REP2, in prenylation of Rab GTPases, key regulators of intracellular vesicular traffic. Here, we report the molecular characterization of 20 unrelated Italian families affected by CHM. We identified 19 different mutations, nine of which are new. In most cases, we analyzed the effect of the mutations at the mRNA level. Furthermore, we demonstrated, by in vitro trancription/translation assays, that the mutated mRNAs produced truncated proteins in all cases but one. In fact, we also identified a nov... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202222 Thu, 08 Sep 2011 04:00:00 +0100 5202222 http://www.medworm.com/index.php?rid=5256165&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21578 AbstractLecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high‐density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL‐cholesterol (HDL‐c) deficiency while heterozygotes have half normal HDL‐c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL‐c to better understand the molecular basis of low HDL‐c in our patients. LCAT was sequenced in 98 patients referred for HDL‐c <5th percentile and in four patients referred for low HDL‐c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5256165 Wed, 07 Sep 2011 04:00:00 +0100 5256165 http://www.medworm.com/index.php?rid=5202230&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21598 In conclusion, CADMA enables highly sensitive and specific mutation detection by HRM analysis. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202230 Wed, 07 Sep 2011 04:00:00 +0100 5202230 http://www.medworm.com/index.php?rid=5202229&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21578 AbstractLecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high‐density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL‐cholesterol (HDL‐c) deficiency while heterozygotes have half normal HDL‐c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL‐c to better understand the molecular basis of low HDL‐c in our patients. LCAT was sequenced in 98 patients referred for HDL‐c <5th percentile and in four patients referred for low HDL‐c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202229 Wed, 07 Sep 2011 04:00:00 +0100 5202229 http://www.medworm.com/index.php?rid=5202228&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21584 AbstractIn some clinical and research settings, it is often necessary to identify the true level of “identity by descent” (IBD) between two individuals. However, as the individuals become more distantly related, it is increasingly difficult to accurately calculate this value. Consequently, we have developed a computer program that uses genome‐wide SNP genotype data from related individuals to estimate the size and extent of IBD in their genomes. In addition, the software can compare a couple's IBD regions with either the autozygous regions of a relative affected by an autosomal recessive disease of unknown cause, or the IBD regions in the parents of the affected relative. It is then possible to calculate the probability of one of the couple's children suffering from the same disease.... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202228 Wed, 07 Sep 2011 04:00:00 +0100 5202228 http://www.medworm.com/index.php?rid=5202227&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21588 AbstractThe Human Variome Project (HVP) is an international consortium of clinicians, geneticists, and researchers from over 30 countries, aiming to facilitate the establishment and maintenance of standards, systems, and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease. The HVP‐China Node will build new and supplement existing databases of genetic diseases. As the first batch of this effort, we have created a novel variant database of BRCA1 and BRCA2, mismatch repair genes (MMR), and APC genes for breast cancer, Lynch syndrome, and familial adenomatous polyposis (FAP), respectively, in the Chinese population using the Leiden Open Variation Database (LOVD) format. We searched PubMed and some Chinese searching engines to collect all ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202227 Wed, 07 Sep 2011 04:00:00 +0100 5202227 http://www.medworm.com/index.php?rid=5202226&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21589 In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified seven rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of five PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild‐type zebrafish prickle1a (zpk1a) in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202226 Wed, 07 Sep 2011 04:00:00 +0100 5202226 http://www.medworm.com/index.php?rid=5202225&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21590 AbstractMicrophthalmia, anophthalmia, and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used single nucleotide polymorphism (SNP) homozygosity mapping (HM) and targeted next‐generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous microanophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double‐nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, includ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202225 Wed, 07 Sep 2011 04:00:00 +0100 5202225 http://www.medworm.com/index.php?rid=5202224&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21587 AbstractIt has been well documented that mutations in the same retinal disease gene can result in different clinical phenotypes due to difference in the mutant allele and/or genetic background. To evaluate this, a set of consanguineous patient families with Leber congenital amaurosis (LCA) that do not carry mutations in known LCA disease genes was characterized through homozygosity mapping followed by targeted exon/whole‐exome sequencing to identify genetic variations. Among these families, a total of five putative disease‐causing mutations, including four novel alleles, were found for six families. These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A. Therefore, in our LCA collection from Saudi Arabia, three of the 37 unassigned families carry mutations in re... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202224 Wed, 07 Sep 2011 04:00:00 +0100 5202224 http://www.medworm.com/index.php?rid=5266899&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21604 AbstractIonizing radiation (IR) is a breast carcinogen that induces DNA double‐strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation‐induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population‐based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location‐specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty‐two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no varian... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5266899 Tue, 06 Sep 2011 04:00:00 +0100 5266899 http://www.medworm.com/index.php?rid=5202234&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21605 AbstractHeterozygous germ‐line mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the BMP pathway, namely SMAD1, SMAD4, SMAD5 and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4 and 9 amongst a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino‐acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202234 Tue, 06 Sep 2011 04:00:00 +0100 5202234 http://www.medworm.com/index.php?rid=5202233&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21604 AbstractIonizing radiation is a breast carcinogen that induces DNA double strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation‐induced breast cancer. The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a population‐based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location‐specific radiation dose received to the contralateral breast was estimated from radiotherapy records and mathematical models. 152 SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases, 1284 controls) and no variants were found to interact with r... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202233 Tue, 06 Sep 2011 04:00:00 +0100 5202233 http://www.medworm.com/index.php?rid=5202232&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21603 In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult‐onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM‐associated BAG3 mutations impaired the Z‐disc assembly and increased the sensitivities to stress‐induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z‐disc assembly and inducing apoptotic cell death under the metabolic stress. ©2011 Wiley‐Liss, Inc. (Source: Human Mutation) Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202232 Tue, 06 Sep 2011 04:00:00 +0100 5202232 http://www.medworm.com/index.php?rid=5202231&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21602 AbstractNext‐generation sequencing (NGS) technologies can be a boon to human mutation detection given their high throughput: consequently, many genes and samples may be simultaneously studied with high coverage for accurate detection of heterozygotes. In circumstances requiring the intensive study of a few genes, particularly in clinical applications, a rapid turn‐around is another desirable goal. To this end, we assessed the performance of the bench‐top 454 GS Junior platform as an optimized solution for mutation detection by amplicon sequencing of three type 3 semaphorin genes SEMA3A, SEMA3C and SEMA3D implicated in Hirschsprung disease (HSCR). We performed mutation detection on 39 PCR amplicons totaling 14,014bp in 47 samples studied in pools of 12 samples. Each 10‐hour run was ... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5202231 Tue, 06 Sep 2011 04:00:00 +0100 5202231 http://www.medworm.com/index.php?rid=5342145&cid=s_33774_50_f&fid=33774&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fhumu.21599 AbstractVery recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndro‐mes. In eight probands with atrioventricular block or right bundle branch block—five familial cases and three spora‐dic cases—a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long‐QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through... Human Mutation journals http://www.medworm.com/rss/comments.php?id=5342145 Thu, 01 Sep 2011 04:00:00 +0100 5342145