HGG Advances最新文献

RNA polymerase III (RNA Pol III)-related disorders (POLR3-RDs) are a group of clinical entities characterized by causal variants in genes encoding RNA Pol III subunits, including POLR3A, POLR3B, POLR1C, POLR1D, POLR3D, POLR3E, POLR3F, POLR3GL, POLR3H, and POLR3K. These typically cause developmental phenotypes affecting the central nervous system; the eyes; connective tissues including bones, teeth, and endocrine axes; and the reproductive system. Similar phenotypes can be caused by variants in separate subunit genes (multigenic). In contrast, variants in the same gene can cause different phenotypes (pleiotropy), making genotype-phenotype correlation challenging. POLR3-RDs, though individually rare, have never been analyzed collectively. To bridge this gap, we developed an extensive database encompassing all published and unpublished cases of POLR3-RDs and conducted the first comprehensive genotype-phenotype correlation study across their entire spectrum. This work contributed new cases, representing 13% of all documented cases in the literature, along with 31 novel variants, accounting for 8% of all identified variants. This database was constructed by systematically reviewing the literature and integrating data from patients under the care of our international network of collaborators. The dataset includes genotype curation, bioinformatics, prior publications, and individual patient outcome information. By leveraging these comprehensive data, we were able to establish clear genotype-phenotype correlations for some pathogenic variants, which will help provide optimal clinical care and genetic counseling (including insights into disease phenotypes and progression) and offer valuable guidance for future clinical trial design and patient stratification.

To date, the KCTD10 gene (MIM: 608726) has not been definitively associated with a human disease, although studies in animal models suggest that it plays a role in embryonic development. We have identified multiple unrelated individuals with de novo missense variants and overlapping phenotypes, including congenital heart anomalies and congenital anomalies in other organ systems, in our internal database. This report includes a detailed description of the genotype and phenotype for two consented individuals and aggregate data of additional individuals who were not available for case-specific publication. Based on the data presented here, we propose that damaging de novo missense KCTD10 variants are associated with an autosomal dominant phenotype that includes cardiac and other congenital anomalies. We encourage additional studies to further characterize this condition and identify a mechanism for disease.

Abdominal hernias are caused by the protrusion of an organ or tissue through a weakened abdominal wall. Genome-wide association studies (GWASs) have identified 81 genetic susceptibility loci for different hernia subtypes, with 26 loci associated with more than one hernia type; however, additional work is needed to prioritize causal genes at known GWAS loci, identify novel ones, and characterize shared genetic effects across hernia subtypes. We conduct transcriptome-wide association study (TWAS) analyses of four hernia subtypes (i.e., inguinal, umbilical, ventral, femoral) using GWAS summary statistics from up to 57,291 hernia cases and 436,717 controls of European ancestry. Our TWAS, which leveraged imputed gene expression from 54 tissues, identifies 211 unique genes, of which 85 did not overlap with known hernia-associated loci. We also investigate patterns of pleiotropy and identify four genes (LYPLAL1-AS1, RIMKLBP2, AL513283.1, and EFEMP1) associated with all four hernia subtypes. Our findings enhance understanding of transcriptomic mechanisms through which hernias develop.

The human X chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X chromosome is understudied. To investigate functional rare variants on the X chromosome, we use observations of outlier gene expression from Genotype Tissue Expression consortium data. We show that outlier genes are enriched for having nearby rare variants on the X chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 733 rare variants in 450 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Overall, we observed more within-sex variation than between-sex variation. Combined, our study investigates functional rare variants on the X chromosome, and further details how sex stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts.

A significant barrier to the treatment of neurodevelopmental disorders (NDDs) is a limited understanding of disease mechanisms. Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease. This study investigated the impact of pathogenic PPP2R5D variants on neuronal development and evaluated allele-specific knockdown as a potential therapeutic strategy. Induced pluripotent stem cells derived from individuals carrying the E198K and E420K variants, along with CRISPR-corrected isogenic controls, were differentiated into neural progenitors and cortical glutamatergic neurons. Patient-derived neural progenitors were hyper-proliferative, and glutamatergic neurons differentiated from these cells exhibited increased neurite outgrowth. Notably, neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function. RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient lines compared to their isogenic controls revealed disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance. To target pathogenic transcripts, antisense oligonucleotides (ASOs) were designed to selectively knock down the E198K allele, the most common disease-causing missense variant. The most effective ASOs reversed neurite outgrowth defects in patient-derived neurons. These findings uncover molecular mechanisms underlying PPP2R5D-related NDDs and support allele-specific knockdown as a potential therapeutic approach.

The total burden of rare diseases is significant worldwide, with over 300 million people being affected. Many rare diseases have both well-defined clinical phenotypes and established genetic causes. However, a remarkable proportion of patients with high clinical suspicion of a rare disease remain genetically undiagnosed and stuck in the diagnostic odyssey after having a cascade of conventional genetic tests. One of the major factors contributing to this is that many types of variants are technically intractable to whole-exome sequencing (WES). In this study, the added diagnostic power of whole-genome sequencing (WGS) for patients with clinically suspected rare diseases was assessed by detecting technically challenging variants. 3,169 patients from the Hong Kong Genome Project (HKGP) were reviewed, identifying 322 individuals having high clinical suspicion of a rare disorder with well-established genetic etiology. Notably, 180 patients have performed at least one previous genetic test. Through PCR-free short-read WGS and a comprehensive in-house analytic pipeline, causative variants were found in 138 patients (138 of 322, 42.9%), 30 of which (30 of 138, 21.7%) are attributed to technically challenging variants. These included 6 variants in low-coverage regions with PCR bias, 2 deep intronic variants, 2 repeat expansions, 19 structural variants, and 2 variants in genes with a homologous pseudogene. The study demonstrated the indispensable diagnostic power of WGS in detecting technically challenging variants and the capability to serve as an all-in-one test for patients with high clinical suspicion of rare diseases.

Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry's impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were (1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; and (2) overall survival (OS), defined as the time from study enrollment to death from any cause. Genetic ancestry was estimated using Grafpop software, and Cox regression assessed the association between genetic ancestry and EFS and OS, considering RMS overall, by fusion status, and by histological subtype. Covariates included sex, age at diagnosis, tumor stage, and histology, except during stratified analyses. In embryonal RMS and PAX3/7:FOXO1 fusion-negative RMS, individuals with South Asian or Asian-Pacific Islander ancestry showed worse EFS (hazard ratio [HR] 2.06, 95% confidence interval [CI] 1.07-3.97, p = 0.03 and HR 2.01, 95% CI 1.07-3.76, p = 0.03, respectively) and OS (HR 2.30, 95% CI 1.09-4.84, p = 0.03 and HR 2.33, 95% CI 1.15-4.70, p = 0.020, respectively) compared to those with primarily European genetic ancestry. These findings suggest that genetic ancestry influences survival outcomes within RMS subtypes, and further understanding may improve precision-medicine-based efforts.

Polygenic risk scores (PRSs) models trained from genome-wide association study (GWAS) results are set to play a pivotal role in biomedical research addressing multifactorial human diseases. The prospect of using these risk scores in clinical care and public health is generating both enthusiasm and controversy, with varying opinions among experts about their strengths and limitations. The performance of existing polygenic scores is still limited but is expected to improve with increasing GWAS sample sizes and the development of new, more powerful methods. Theoretically, the variance explained by PRS can be as high as the total additive genetic variance, but it is unclear how much of that variance has already been captured by PRS. Here, we conducted a retrospective analysis to assess progress in PRS prediction accuracy since the publication of the first large-scale GWASs, using data from six common human diseases with sufficient GWAS information. We show that although PRS accuracy has grown rapidly over the years, the pace of improvement from recent GWAS has decreased substantially, suggesting that merely increasing GWAS sample sizes may lead to only modest improvements in risk discrimination. We next investigated the factors influencing the maximum achievable prediction using whole-genome sequencing data from 125,000 UK Biobank participants and state-of-the-art modeling of polygenic outcomes. Our analyses suggest that increasing the variant coverage of PRS, using either more imputed variants or sequencing data, is a key component for future improvements in prediction accuracy.

This systematic review and meta-analysis examined the prevalence and clinical impact of germline variants in small cell lung cancer (SCLC). Primary objectives included estimating the prevalence of germline variants in SCLC patients, while secondary objectives focused on their effects on patient outcomes. A comprehensive search was conducted in Ovid MEDLINE, EMBASE, and gray-literature databases (as of July 2024). Studies reporting germline variants in SCLC patients were included. Data were extracted to calculate pooled prevalence and hazard ratios (HRs). Study quality was assessed using the Translating ROBBINs tool, and heterogeneity was evaluated using the I² statistic. Of 6,117 screened studies, 124 met inclusion criteria, with 8% (10/124) reporting pathogenic/likely pathogenic (P/LP) findings. Meta-analysis using a random-effects model estimated the prevalence of P/LP germline variants in SCLC patients at 11% (95% CI: 5%-25%). Gene-level prevalence was estimated for ATM (pooled prevalence = 1%; 95% CI: 0%-5%), BRCA1 (1%; 95% CI: 1%-3%), BRCA2 (1%; 95% CI: 1%-3%), and TP53 (1%; 95% CI: 0%-3%). Patients with P/LP variants in DNA damage repair genes showed a non-significant prognostic survival benefit (pooled HR: 0.8; 95% CI: 0.51-1.29, I² = 8%). We have conducted a comprehensive systematic review of germline variants and their impact on clinical outcomes of SCLC patients. Our meta-analysis identified an estimated prevalence of P/LP variants in SCLC patients, suggesting a rationale for screening in the clinic.