The natural history and genotype –phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis
AbstractTMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 uniqueTMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-coch...
Source: Human Genetics - April 30, 2024 Category: Genetics & Stem Cells Source Type: research
Chromatinopathies – from discovery to clinical diagnosis in the real world
(Source: Human Genetics)
Source: Human Genetics - April 26, 2024 Category: Genetics & Stem Cells Source Type: research
A novel network-based method identifies a cuproplasia-related pan-cancer gene signature to predict patient outcome
AbstractCopper is a vital micronutrient involved in many biological processes and is an essential component of tumour cell growth and migration. Copper influences tumour growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival. Utilising RNA-sequencing ...
Source: Human Genetics - April 20, 2024 Category: Genetics & Stem Cells Source Type: research
Examination of the shared genetic architecture between multiple sclerosis and systemic lupus erythematosus facilitates discovery of novel lupus risk loci
AbstractSystemic Lupus Erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including neurological and psychiatric symptoms. Genetic association studies in SLE have been hampered by insufficient sample size and limited power compared to many other diseases. Multiple Sclerosis (MS) is a chronic relapsing autoimmune disease of the central nervous system (CNS) that also manifests neurological and immunological features. Here, we identify a method of leveraging large-scale genome wide association studies (GWAS) in MS to identify novel genetic risk loci in SLE. Statistical genetic comparison methods i...
Source: Human Genetics - April 12, 2024 Category: Genetics & Stem Cells Source Type: research
VARista: a free web platform for streamlined whole-genome variant analysis across T2T, hg38, and hg19
AbstractWith the increasing importance of genomic data in understanding genetic diseases, there is an essential need for efficient and user-friendly tools that simplify variant analysis. Although multiple tools exist, many present barriers such as steep learning curves, limited reference genome compatibility, or costs. We developed VARista, a free web-based tool, to address these challenges and provide a streamlined solution for researchers, particularly those focusing on rare monogenic diseases. VARista offers a user-centric interface that eliminates much of the technical complexity typically associated with variant analy...
Source: Human Genetics - April 12, 2024 Category: Genetics & Stem Cells Source Type: research
Loss-of-function variants affecting the STAGA complex component SUPT7L cause a developmental disorder with generalized lipodystrophy
AbstractGeneralized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state inSUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features.SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we fou...
Source: Human Genetics - April 9, 2024 Category: Genetics & Stem Cells Source Type: research
Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke
AbstractWhile carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (A...
Source: Human Genetics - April 5, 2024 Category: Genetics & Stem Cells Source Type: research
Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy
We examined the functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry, and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified, with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI, while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstem hypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4 ’s heterodimerization capability with ClC-3 and suppressed anion...
Source: Human Genetics - April 5, 2024 Category: Genetics & Stem Cells Source Type: research
Prioritizing genomic variants pathogenicity via DNA, RNA, and protein-level features based on extreme gradient boosting
In this study, we have curated DNA-, RNA-, and protein-level features to discriminate disease-causing variants in both coding and noncoding regions, where the features of protein sequences and protein structures have been shown essential for analyzing missense variants in coding regions while the features related to RNA-splicing and RBP binding are significant for variants in noncoding regions and synonymous variants in coding regions. Through the integration of these features, we have formulated the Multi-level feature Genomic Variants Predictor (ML-GVP) using the gradient boosting tree. The method has been trained on mor...
Source: Human Genetics - April 4, 2024 Category: Genetics & Stem Cells Source Type: research
Variant effect predictors: a systematic review and practical guide
AbstractLarge-scale association analyses using whole-genome sequence data have become feasible, but understanding the functional impacts of these associations remains challenging. Although many tools are available to predict the functional impacts of genetic variants, it is unclear which tool should be used in practice. This work provides a practical guide to assist in selecting appropriate tools for variant annotation. We conducted a MEDLINE search up to November 10, 2023, and included tools that are applicable to a broad range of phenotypes, can be used locally, and have been recently updated. Tools were categorized base...
Source: Human Genetics - April 4, 2024 Category: Genetics & Stem Cells Source Type: research
Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data
We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process. (Source: Human Genetics)
Source: Human Genetics - March 27, 2024 Category: Genetics & Stem Cells Source Type: research
Cross-ancestry genetic architecture and prediction for cholesterol traits
AbstractWhile cholesterol is essential, a high level of cholesterol is associated with the risk of cardiovascular diseases. Genome-wide association studies (GWASs) have proven successful in identifying genetic variants that are linked to cholesterol levels, predominantly in white European populations. However, the extent to which genetic effects on cholesterol vary across different ancestries remains largely unexplored. Here, we estimate cross-ancestry genetic correlation to address questions on how genetic effects are shared across ancestries. We find significant genetic heterogeneity between ancestries for cholesterol tr...
Source: Human Genetics - March 27, 2024 Category: Genetics & Stem Cells Source Type: research
The crucial prognostic signaling pathways of pancreatic ductal adenocarcinoma were identified by single-cell and bulk RNA sequencing data
AbstractPancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis and high mortality. Although a large number of studies have explored its potential prognostic markers using traditional RNA sequencing (RNA-Seq) data, they have not achieved good prediction effect. In order to explore the possible prognostic signaling pathways leading to the difference in prognosis, we identified differentially expressed genes from one scRNA-seq cohort and four GEO cohorts, respectively. Then Cox and Lasso regression analysis showed that 12 genes were independent prognostic factors for PDAC. AUC and calibration curve a...
Source: Human Genetics - March 25, 2024 Category: Genetics & Stem Cells Source Type: research
Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly
AbstractNeurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation ofRAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants inDOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, m...
Source: Human Genetics - March 25, 2024 Category: Genetics & Stem Cells Source Type: research
Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder
AbstractGeneral transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants inGTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism....
Source: Human Genetics - March 23, 2024 Category: Genetics & Stem Cells Source Type: research
