The accuracy of computer ‐based diagnostic tools for the identification of concurrent genetic disorders
The increasing use of next ‐generation sequencing, especially clinical exome sequencing, has revealed that individuals having two coexisting genetic conditions are not uncommon occurrences. This pilot study evaluates the efficacy of two methodologically distinct computational differential diagnosis generating tools—FindZe bra and SimulConsult—in identifying multiple genetic conditions in a single patient. Clinical query terms were generated for each of 15 monogenic disorders that were effective in resulting in the top 10 list of differential diagnoses for each of the 15 monogenic conditions when entered into these bi...
Source: American Journal of Medical Genetics Part A - November 26, 2018 Category: Genetics & Stem Cells Authors: Raoul R. Wadhwa, Deborah Y. Park, Marvin R. Natowicz Tags: RESEARCH ARTICLE Source Type: research

Gain ‐of‐function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities
In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain‐of‐function variants in theODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow –Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation ofN‐acetylputrescine, the acetylated form of putrescine, with ...
Source: American Journal of Medical Genetics Part A - November 26, 2018 Category: Genetics & Stem Cells Authors: Lance H. Rodan, Kwame Anyane ‐Yeboa, Karen Chong, Jolien S. Klein Wassink‐Ruiter, Ashley Wilson, Lacey Smith, Sanjeev V. Kothare, Farrah Rajabi, Susan Blaser, Min Ni, Ralph J. DeBerardinis, Annapurna Poduri, Gerard T. Berry Tags: RESEARCH ARTICLE Source Type: research

Unmasking familial CPX by WES and identification of novel clinical signs
This study emphasiz es the importance of WES analysis in familial CLP cases, combined with deep (reverse) phenotyping in “a priori” non‐syndromic clefts. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2018 Category: Genetics & Stem Cells Authors: B énédicte Demeer, Nicole Revencu, Raphael Helaers, Bernard Devauchelle, Geneviève François, Bénédicte Bayet, Miikka Vikkula Tags: RESEARCH ARTICLE Source Type: research

Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy
We report a 9 ‐year‐old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio‐based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in theBRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this a...
Source: American Journal of Medical Genetics Part A - November 21, 2018 Category: Genetics & Stem Cells Authors: Lidia Pezzani, Daniela Marchetti, Anna Cereda, Lorella G. Caffi, Ornella Manara, Daniela Mamoli, Laura Pezzoli, Anna R. Lincesso, Loredana Perego, Isabella Pellicioli, Ezio Bonanomi, Laura Salvoni, Maria Iascone Tags: CLINICAL REPORT Source Type: research

Japanese patient with Cole ‐carpenter syndrome with compound heterozygous variants of SEC24D
We describe a 15‐year‐old Japanese boy with short stature of the short‐trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole‐Carpenter syndrome. He had low‐bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants inSEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants ofSEC24D causing Cole ‐Carpenter syndrome type 2. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2018 Category: Genetics & Stem Cells Authors: Shinji Takeyari, Takuo Kubota, Kei Miyata, Kenichi Yamamoto, Hirofumi Nakayama, Keiko Yamamoto, Yasuhisa Ohata, Taichi Kitaoka, Kumiko Yanagi, Tadashi Kaname, Keiichi Ozono Tags: CLINICAL REPORT Source Type: research

First reported adult patient with TARP syndrome: A case report
TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X ‐linked syndrome often resulting in pre‐ or post‐natal lethality in affected males. In 2010,RBM10 was identified as the disease ‐causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome. In addition, he had a prominent nose and nasal bridge, esotropia, displace...
Source: American Journal of Medical Genetics Part A - November 21, 2018 Category: Genetics & Stem Cells Authors: Allan T. H øjland, Ihab Lolas, Henrik Okkels, Charlotte K. Lautrup, Birgitte R. Diness, Michael B. Petersen, Irene K. Nielsen Tags: CLINICAL REPORT Source Type: research

A retrospective study on sleep ‐disordered breathing in Morquio‐A syndrome
Respiratory problems are common in Morquio ‐A syndrome (MPS IVA) but objective data on sleep‐disordered breathing are scarce. The aim of our study was to review polygraphic (PG) findings and the need for noninvasive continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in children with MPS IVA. A retrospective revie w of the clinical charts and PG of 16 consecutive children (7 boys, mean age 10.5 ± 4.2 years) with MPS IVA seen over a period of 3 years was performed. The prevalence of obstructive sleep apnea (OSA) was 69% with only five patients, all younger than 10 years old, having a normal ...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Giulia Facchina, Alessandro Amaddeo, Genevi ève Baujat, Sylvain Breton, Caroline Michot, Briac Thierry, Syril James, Timothé de Saint Denis, Michel Zerah, Sonia Khirani, Valerie Cormier‐Daire, Brigitte Fauroux Tags: ORIGINAL ARTICLE Source Type: research

Two unrelated individuals carrying rare mosaic deletions in TCF4 gene
American Journal of Medical Genetics Part A, EarlyView. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Ludmila Kousoulidou, Angelos Alexandrou, Ioannis Papaevripidou, Paola Evangelidou, George Tanteles, Violetta C. Anastasiadou, Carolina Sismani Tags: RESEARCH LETTER Source Type: research

Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma
In this report we describe six new cases, four of which carry novel pathogenicSOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation inSOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novoSOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow ‐growing hypothalamo‐pituitary...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Patrick R. Blackburn, Oscar F. Chacon ‐Camacho, Xilma R. Ortiz‐González, Mariana Reyes, Graciela A. Lopez‐Uriarte, Shabnam Zarei, Elizabeth J. Bhoj, Sofia Perez‐Solorzano, Rachael A. Vaubel, Marine I. Murphree, Jessica Nava, Vianney Co Tags: RESEARCH ARTICLE Source Type: research

Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution
The TWIST family is a group of highly conserved basic helix –loop–helix transcription factors. In humans,TWIST1 haploinsufficiency causes Saethre –Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localizedTWIST1 andTWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney –Cox syndrome, Barber–Say syndrome, and ablepharon‐macrostomia syndrome, respectively. Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon‐macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the co rners...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Toshiki Takenouchi, Yoshiaki Sakamoto, Hironori Sato, Hisato Suzuki, Tomoko Uehara, Yoshiteru Ohsone, Kenjiro Kosaki Tags: CLINICAL REPORT Source Type: research

Infant male with TARP syndrome: Review of clinical features, prognosis, and commonalities with previously reported patients
TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava) is a rare X ‐linked condition. As more patients are identified through genetic testing, it is increasingly clear that the original TARP acronym does not fully describe the complete phenotypic spectrum of this syndrome. The presented patient had genetically confirmed TARP syndrome and demonstrated new findings of hydronephrosis and hemodynamically significant hypertrophic obstructive cardiomyopathy. The patient also had physical findings common with previously reported individuals with TARP syndrome in the lit...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Kathrine E. Kaeppler, Raymond C. Stetson, Brendan C. Lanpher, Christopher A. Collura Tags: CLINICAL REPORT Source Type: research

An additional case of Hennekam lymphangiectasia –lymphedema syndrome caused by loss‐of‐function mutation in ADAMTS3
Hennekam lymphangiectasia –lymphedema syndrome (HKLLS) is a genetically heterogeneous lymphatic dysplasia with characteristic of facial dysmorphism, neurocognitive impairments, and abnormalities of the pericardium, intestinal tract, and extremities. It is an autosomal recessive condition caused by biallelic mutations inCCBE1 (collagen ‐ and calcium‐binding epidermal growth factor domain‐containing protein 1) (HKLLS1; OMIM 235510) orFAT4 (HKLLS2; OMIM 616006). CCBE1 acts via ADAMTS3 (a disintegrin and metalloprotease with thrombospondin motifs ‐3 protease) to enhance vascular endothelial growth factor C signaling....
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Angela E. Scheuerle, Nathan T. Sweed, Charles F. Timmons, Erica D. Smith, Wendy A. Alcaraz, Deepali N. Shinde Tags: CLINICAL REPORT Source Type: research

Microphthalmia is not a mandatory finding in X ‐linked recessive syndromic microphthalmia caused by the recurrent BCOR variant p.Pro85Leu
Mutations inBCOR cause X ‐linked dominant and X‐linked recessive forms of syndromic microphthalmia. By exome sequencing, we identified the recurrentBCOR mutation p.Pro85Leu in two brothers and their unaffected mother. While the older brother's phenotype completely fits the described phenotypic spectrum of X ‐linked recessiveBCOR‐associated Lenz microphthalmia syndrome, the younger brother showed developmental delay, microcephaly, and skeletal anomalies, but not the key feature of microphthalmia. In contrast to the previously published families, our findings demonstrate a large variability ofBCOR‐associated, syndr...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Cornelia Kraus, Steffen Uebe, Christian T. Thiel, Arif B. Ekici, Andr é Reis, Christiane Zweier Tags: CLINICAL REPORT Source Type: research

Next generation sequencing ‐based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes
In this study, we used commercially available inherited disease NGS panels including 50 CC genes for the genetic diagnosis of 11 probands with hereditary CC. Causal variants were recognized in six families. A novelCRYGC variant, p.(Phe6Ser), was identified in two apparently unrelated families. Two additional novel variants in the crystallin genesCRYBB2 (p.[Gly149Asp]) andCRYGA (p.[Arg48Cys]) were also identified. One family carried the novel p.[Gly8_Leu11del] variant inGJA8, while another family exhibited the previously reported c.2826 ‐9G>A pathogenic change inEPHA2. Our results illustrate the utility of NGS for diag...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Mirena C. Astiazar án, Leopoldo A. García‐Montaño, Francisco Sánchez‐Moreno, Humberto Matiz‐Moreno, Juan C. Zenteno Tags: RESEARCH ARTICLE Source Type: research

Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation
We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation inCOL9A3, which encodes the α3 chain of type IX procollagen. The clinical features were similar to the previously describedCOL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the α3 chain of ty...
Source: American Journal of Medical Genetics Part A - November 18, 2018 Category: Genetics & Stem Cells Authors: Andrea Hanson ‐Kahn, Bing Li, Daniel H. Cohn, Deborah A. Nickerson, Michael J. Bamshad, University of Washington Center for Mendelian Genomics, Louanne Hudgins Tags: CLINICAL REPORT Source Type: research