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
An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases
AbstractIdentifying disease-causing variants in Rare Disease patients ’ genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called “Suggested Diagnosis”, whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality. Starting from (1) the VCF file co...
Source: Human Genetics - March 23, 2024 Category: Genetics & Stem Cells Source Type: research
An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population
AbstractMeniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9 –10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described,OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that anOTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution ofOTOG rare variants across different populations. Fo...
Source: Human Genetics - March 22, 2024 Category: Genetics & Stem Cells Source Type: research
Genetic evidence for T-wave area from 12-lead electrocardiograms to monitor cardiovascular diseases in patients taking diabetes medications
ConclusionPatients taking diabetes medications are prone to have decreased aVR_T-area and an increased risk of IHD and CA. The aVR_T-area is therefore a potential ECG marker for pre-clinical prediction of IHD and CA in patients taking diabetes medications. (Source: Human Genetics)
Source: Human Genetics - March 20, 2024 Category: Genetics & Stem Cells Source Type: research
