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
Identification of potential disease-associated variants in idiopathic generalized epilepsy using targeted sequencing
AbstractMany questions remain regarding the genetics of idiopathic generalized epilepsy (IGE), a subset of genetic generalized epilepsy (GGE). We aimed to identify the candidate coding variants of epilepsy panel genes in a cohort of affected individuals, using variant frequency information from a control cohort of the same region. We performed whole-exome sequencing analysis of 121 individuals and 10 affected relatives, focusing on variants of 950 candidate genes associated with epilepsy according to the Genes4Epilepsy curated panel. We identified 168 candidate variants (CVs) in 137 of 950 candidate genes in 88 of 121 affe...
Source: Journal of Human Genetics - November 22, 2023 Category: Genetics & Stem Cells Source Type: research
Nanopore long-read sequencing analysis reveals ZIC1 dysregulation caused by a de novo 3q inversion with a breakpoint located 7 kb downstream of ZIC1
This study highlights the usefulness of long-read sequencing in the analysis of de novo balanced chromosomal abnormalities. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - November 10, 2023 Category: Genetics & Stem Cells Source Type: research
Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK
This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - November 1, 2023 Category: Genetics & Stem Cells Source Type: research
Integrated omics analyses clarifies ATRX copy number variant of uncertain significance
We describe an affected male with a de novo hemizygous intragenic duplication of ~43.6 kb inATRX, detected by research genome sequencing following non-diagnostic clinical testing. RNA sequencing and DNA methylation episignature analyses were central in variant interpretation, and this duplication was subsequently interpreted as disease-causing. This represents the smallest reported tandem duplication withinATRX associated with disease. This case demonstrates the diagnostic utility of integrating multiple omics technologies, which can ultimately lead to a definitive diagnosis for rare disease patients. (Source: Journal of Human Genetics)
Source: Journal of Human Genetics - October 31, 2023 Category: Genetics & Stem Cells Source Type: research
JHG Young Scientist Award 2023
(Source: Journal of Human Genetics)
Source: Journal of Human Genetics - October 31, 2023 Category: Genetics & Stem Cells Source Type: research
Preimplantation genetic testing using comprehensive genomic copy number analysis is beneficial for balanced translocation carriers
This study aimed to verify whether and how embryos from couples in which one partner is a balanced translocation carrier have a higher ratio of chromosomal abnormalities. A total of 894 biopsied trophectoderms (TEs) were obtained from 130 couples in which one partner was a balanced translocation carrier (Robertsonian translocation, reciprocal translocation, or intrachromosomal inversion) and grouped as PGT-SR. Conversely, 3269 TEs from 697 couples who experienced recurrent implantation failure or recurrent pregnancy loss were included in the PGT-A group. The transferable blastocyst ratio was significantly lower in the PGT-...
Source: Journal of Human Genetics - October 23, 2023 Category: Genetics & Stem Cells Source Type: research
Two novel CHN1 variants identified in Duane retraction syndrome pedigrees disrupt development of ocular motor nerves in zebrafish
In this study, we enrolled two unrelated pedigrees with DRS. Detailed clinical examinations, MRI, and the whole exome sequencing (WES) were performed to reveal their clinical and genetic characteristics. Patients from pedigree-1 presented with isolated DRS, and a novel heterozygous variant c.650 A > G, p. His217Arg was identified inCHN1 gene. Patients from pedigree-2 presented with classic DRS and abnormalities in auricle morphology, and the pedigree segregated another novel heterozygousCHN1 variant c.637 T > C, p. Phe213Leu. A variety of bioinformatics software predicted that the two variants had del...
Source: Journal of Human Genetics - October 18, 2023 Category: Genetics & Stem Cells Source Type: research
Angiogenesis related genes in Takayasu Arteritis (TAK): robust association with Tag SNPs of IL-18 and FGF-2 in a South Asian Cohort
AbstractWe performed genetic association study for genes encoding angiogenic and angiostatic proteins in patients with Takayasu arteritis (TAK). A total of 96 SNPs involving 60 genes were studied. Genotyping was performed in Fluidigm 96.96 Dynamic Array chip. All statistical analysis for SNP evaluation was performed using PLINK software. Initial analyses revealed five SNPs from three genes [IL-18 (encodes Interleukin-18),FGF2 (encodes Fibroblast Growth Factor-2), andANGPT1 (encodes Angiopoietin-1)] as significantly different between controls and cases (uncorrectedp < 0.05). After permutation-based analysis, two tag...
Source: Journal of Human Genetics - October 17, 2023 Category: Genetics & Stem Cells Source Type: research
Prevalence of repeat expansions causing autosomal dominant spinocerebellar ataxias in Hokkaido, the northernmost island of Japan
In this study, we investigated the status of AD-SCD mainly due to repeat expansions, covering the period since the last report. We performed genetic analysis for 312 patients with a clinical diagnosis of SCD, except for multiple system atrophy at medical institutions in Hokkaido between January 2007 and December 2020. The median age at the time of analysis was 58 (1 –86) years. Pathogenic variants causing AD-SCD due to repeat expansion were found in 61.5% (192 cases). Spinocerebellar ataxia (SCA) 6 was the most common type in 25.3% (79 cases), followed by Machado-Joseph disease (MJD)/SCA3 in 13.8% (43), SCA1 in 6.4% (20)...
Source: Journal of Human Genetics - October 17, 2023 Category: Genetics & Stem Cells Source Type: research
Analysis of complex chromosomal rearrangement involving chromosome 6 via the integration of optical genomic mapping and molecular cytogenetic methodologies
In this study, we explored a familial CCR involving chromosome 6 by combining optical genomic mapping (OGM) and molecular cytogenetic methodologies. Within this family, the father and the paternal grandfather were both asymptomatic carriers of an identical balanced CCR, while the two offspring with an unbalanced paternal-origin CCR and two microdeletions presented with clinical manifestation. The first affected child, a 5-year-old boy, exhibited neurodevelopmental delay, while the second, a fetus, presented with hydrops fetalis. SNP-genotype analysis revealed a recombination event during gamete formation in the father that...
Source: Journal of Human Genetics - October 11, 2023 Category: Genetics & Stem Cells Source Type: research
Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle
AbstractHeterozygous deleterious variants inSKI cause Shprintzen –Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis h ampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p.[Thr180Met]SKI variants were studied combining in silico and in vitro approach. 3D comparative modeling an...
Source: Journal of Human Genetics - September 12, 2023 Category: Genetics & Stem Cells Source Type: research
