Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes
ConclusionOur findings highlight the significance ofZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - February 6, 2024 Category: Genetics & Stem Cells Source Type: research
Cardiac manifestations of human ACTA2 variants recapitulated in a zebrafish model
AbstractTheACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in theACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in t...
Source: Journal of Human Genetics - February 5, 2024 Category: Genetics & Stem Cells Source Type: research
Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability
In this study, we identified novel compound heterozygousABCA2 variants (NM_001606.5:c.[5300 –17C>A];[6379C>T]) by whole exome sequencing in a 28-year-old Korean female patient with intellectual disability. These variants included intronic and nonsense variants of paternal and maternal origin, respectively, and are absent from gnomAD. SpliceAI predicted that the intron variant creates a cryptic acceptor site. Reverse transcription-PCR using RNA extracted from a lymphoblastoid cell line of the patient confirmed two aberrant transcripts. Her clinical features are compatible with those of IDPOGSA. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - January 17, 2024 Category: Genetics & Stem Cells Source Type: research
A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene
We described here a case with riboflavin responsive LSM and MADD resulting fromFLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro,FLAD1-RRMADD). And we compared our patient together with 9FLAD1-RRMADD cases from literature to 106ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study onFLAD1-RRMADD andETFDH-RRMADD were carried out. On muscle pathology, bothFLAD1-RRMADD andETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequen...
Source: Journal of Human Genetics - January 17, 2024 Category: Genetics & Stem Cells Source Type: research
Genotype imputation methods for whole and complex genomic regions utilizing deep learning technology
AbstractThe imputation of unmeasured genotypes is essential in human genetic research, particularly in enhancing the power of genome-wide association studies and conducting subsequent fine-mapping. Recently, several deep learning-based genotype imputation methods for genome-wide variants with the capability of learning complex linkage disequilibrium patterns have been developed. Additionally, deep learning-based imputation has been applied to a distinct genomic region known as the major histocompatibility complex, referred to as HLA imputation. Despite their various advantages, the current deep learning-based genotype impu...
Source: Journal of Human Genetics - January 15, 2024 Category: Genetics & Stem Cells Source Type: research
CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy
This study expands the mutational spectrum ofCRYAB and deepens our understanding of the complex phenotypes of alpha-B crystallinopathies. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - January 12, 2024 Category: Genetics & Stem Cells Source Type: research
Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling
AbstractAromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter disorder caused by pathogenic DOPA decarboxylase (DDC) variants. We previously reported Japanese siblings with AADC deficiency, which was confirmed by the lack of enzyme activity; however, only a heterozygous missense variant was detected. We therefore performed targeted long-read sequencing by adaptive sampling to identify any missing variants. Haplotype phasing and variant calling identified a novel deep intronic variant (c.714+255 C > A), which was predicted to potentially activate the noncanonical splicin...
Source: Journal of Human Genetics - January 12, 2024 Category: Genetics & Stem Cells Source Type: research
C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations
AbstractIQSEC2 gene on chromosome Xq11.22 encodes a member of guanine nucleotide exchange factor (GEF) protein that is implicated in the activation of ADP-ribosylation factors (Arfs) at the postsynaptic density (PSD), and plays a crucial role in synaptic transmission and dendritic spine formation. Alterations inIQSEC2 have been linked to X-linked intellectual developmental disorders including epilepsy and behavioral abnormalities. Of interest, truncating variants at the C-terminus of IQSEC2 can cause severe phenotypes, akin to truncating variants located in other regions. Here, we present a 5-year-old boy with severe intel...
Source: Journal of Human Genetics - January 10, 2024 Category: Genetics & Stem Cells Source Type: research
Prediction of protein structure and AI
This article provides an overview of the 3D structural modeling of AlphaFold based on deep learning techniques and highlights the challenges in predicting the pathogenicity of missense mutations. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - January 4, 2024 Category: Genetics & Stem Cells Source Type: research
Carrier screening for present disease prevalence and recessive genetic disorder in Taiwanese population
In conclusions, the variants in LDLR, GAA and ATP7B genes were identified in Taiwanese population, indicating individuals had higher risk of Pompe disease, Wilson ’s disease and familial hypercholesterolemia. Taiwanese individuals carrying GJB2 and GJB6 had the considerable risk of hearing loss passing to their offspring. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - December 22, 2023 Category: Genetics & Stem Cells Source Type: research
An update and frequency distribution of Y chromosome haplogroups in modern Japanese males
AbstractJapanese males belong to the Y chromosome C1a1, C2, D1a2a, D1a2a-12f2b, O1b2, O1b2a1a1, O2a2b1, and O2a1b haplogroups. Notably, the regional frequency of each haplogroup is homogeneous. Owing to recent developments in genome sequencing technology, the phylogenetic tree of Y chromosome haplogroups is updated annually. Therefore, in this study, we aimed to provide an update on the Y chromosome haplogroups of modern Japanese males and examine their regional distributions. Using 1,640 samples of Japanese males from seven Japanese cities (Nagasaki, Fukuoka, Tokushima, Osaka, Kanazawa, Kawasaki, and Sapporo), haplogroups...
Source: Journal of Human Genetics - December 21, 2023 Category: Genetics & Stem Cells Source Type: research
RNA sequencing and target long-read sequencing reveal an intronic transposon insertion causing aberrant splicing
AbstractMore than half of cases with suspected genetic disorders remain unsolved by genetic analysis using short-read sequencing such as exome sequencing (ES) and genome sequencing (GS). RNA sequencing (RNA-seq) and long-read sequencing (LRS) are useful for interpretation of candidate variants and detection of structural variants containing repeat sequences, respectively. Recently, adaptive sampling on nanopore sequencers enables target LRS more easily. Here, we present a Japanese girl with premature chromatid separation (PCS)/mosaic variegated aneuploidy (MVA) syndrome. ES detected a known pathogenic maternal heterozygous...
Source: Journal of Human Genetics - December 15, 2023 Category: Genetics & Stem Cells Source Type: research
A heterozygous germline deletion within USP8 causes severe neurodevelopmental delay with multiorgan abnormalities
In this study, we investigated an exome-negative patient with severe developmental delay, dysmorphic features, and multiorgan dysfunction by long-read sequencing, and identified a 22-kb de novo germline deletion withinUSP8 (chr15:50469966-50491995 [GRCh38]). The deletion involved the variant hotspot, one rhodanese domain, and two SH3 binding motifs, and was presumed to be generated through nonallelic homologous recombination throughAlu elements. Thus, the patient may have perturbation of the endosomal sorting system and mitochondrial autophagy through theUSP8 defect. This is the second reported case of a germline variant i...
Source: Journal of Human Genetics - November 30, 2023 Category: Genetics & Stem Cells Source Type: research
A missense variant in EXOSC8 causes exon skipping and expands the phenotypic spectrum of pontocerebellar hypoplasia type 1C
This study presents the fifth family with this extremely rare type of PCH and expands the associated clinical and brain imaging findings. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - November 29, 2023 Category: Genetics & Stem Cells Source Type: research
Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders
AbstractSLC5A6 encodes the sodium-dependent multivitamin transporter, a transmembrane protein that uptakes biotin, pantothenic acid, and lipoic acid. BiallelicSLC5A6 variants cause sodium-dependent multivitamin transporter deficiency (SMVTD) and childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), which both respond well to replacement therapy with the above three nutrients. SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy. Without nutrient replacement therapy, SMVTD can be lethal in ...
Source: Journal of Human Genetics - November 27, 2023 Category: Genetics & Stem Cells Source Type: research
