HGG Advances最新文献

{"title":"Two-sample bi-directional causality between two traits with some invalid IVs in both directions using GWAS summary statistics.","authors":"Siyi Chen","doi":"10.1016/j.xhgg.2025.100449","DOIUrl":"10.1016/j.xhgg.2025.100449","url":null,"abstract":"<p><p>Mendelian randomization (MR) is a widely used method for assessing causal relationships between risk factors and outcomes using genetic variants as instrumental variables (IVs). While traditional MR assumes uni-directional causality, bi-directional MR aims to identify the true causal direction. In uni-directional MR, invalid IVs due to pleiotropy can violate assumptions and introduce biases. In bi-directional MR, traditional MR can be performed separately for each direction, but the presence of invalid IVs poses even greater challenges. We introduce a new bi-directional MR method incorporating stepwise selection (Bidir-SW) designed to address these challenges. Our approach leverages public genome-wide association study (GWAS) datasets for two traits and uses model selection criteria to identify invalid IVs iteratively by stepwise selection. This method accounts for potential bi-directional causality in the presence of common invalid IVs for both directions, even if only GWAS summary statistics are provided. Through simulation studies, we demonstrate that our method outperforms traditional MR techniques, such as MR-Egger and inverse-variance weighted (IVW), with uncorrelated SNPs. We also provide simulations to compare our approach with existing transcriptome-wide association study (TWAS) to show its effectiveness. Finally, we apply the proposed method to genetic traits such as CRP levels and BMI to explore possible bi-directional relationships among these traits. We also used the proposed method to discover causal protein biomarkers. Our findings suggest that the Bidir-SW approach is a powerful tool for bi-directional MR or TWAS, which can provide a valuable framework for future genetic epidemiology studies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100449"},"PeriodicalIF":3.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating spatial transcriptomics and snRNA-seq data enhances differential gene expression analysis results of AD-related phenotypes.","authors":"Shizhen Tang, Shihan Liu, Aron S Buchman, David A Bennett, Philip L De Jager, Jingjing Yang, Jian Hu","doi":"10.1016/j.xhgg.2025.100447","DOIUrl":"10.1016/j.xhgg.2025.100447","url":null,"abstract":"<p><p>Spatial transcriptomics (ST) data provide spatially informed gene expression profiles. However, power is limited for spatially informed differential gene expression (DGE) of complex diseases such as Alzheimer disease (AD), due to small sample sizes of ST data. Conversely, single-nucleus RNA sequencing (snRNA-seq) data offer larger sample sizes for cell-type-specific (CTS) analyses but lack spatial information. Here, we integrated ST and snRNA-seq data to enhance the power of spatially informed CTS DGE analysis of AD-related phenotypes. We first utilized the CeLEry tool to infer six cortical layers of ∼1.5 million cells in the snRNA-seq data that were profiled from the dorsolateral prefrontal cortex (DLPFC) tissue of 436 postmortem brains. Then, we conducted cortical layer- and cell-type-specific (LCS) and CTS DGE analyses based on the linear mixed model, for β-amyloid, tangle density, and cognitive decline. We identified 138 LCS significant genes with false discovery rate (FDR) q <0.05, including 103 for β-amyloid, 24 for tangle density, and 25 for cognitive decline. The majority of these LCS significant genes, including known AD risk genes such as APOE, KCNIP3, and CTSD, cannot be detected by CTS analyses. We also identified 2 genes shared across all 3 phenotypes and 10 shared between 2 phenotypes. Gene set enrichment analyses with the LCS DGE results of microglia in cortical layer 6 of β-amyloid identified 12 significant AD-related pathways. In conclusion, incorporating spatial information with snRNA-seq data enhanced the power of spatially informed DGE analyses. These identified LCS significant genes not only help illustrate the pathogenesis of AD but they also provide potential targets for developing therapeutics of AD.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100447"},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aortic valve-specific genes dysregulated in calcific aortic valve stenosis as potential biomarkers and therapeutic targets.","authors":"Pardis Zamani, Ursula Houessou, Hasanga D Manikpurage, Zhonglin Li, Manel Dahmene, Nathalie Gaudreault, François Dagenais, Marie-Annick Clavel, Philippe Pibarot, Benoit J Arsenault, Patrick Mathieu, Yohan Bossé, Sébastien Thériault","doi":"10.1016/j.xhgg.2025.100448","DOIUrl":"10.1016/j.xhgg.2025.100448","url":null,"abstract":"<p><p>Calcific aortic valve stenosis (CAVS) is the most frequent heart valve disease. Elucidating specific gene expression patterns in the aortic valve could provide new insights for understanding disease pathophysiology. We used local RNA sequencing data from 500 explanted human aortic valves to identify aortic valve-specific genes and compared their expression according to disease status and CAVS severity. We identified 100 specific protein-coding genes in the aortic valve compared to 45 other tissues from the Genotype-Tissue Expression (GTEx) project. Among them, 38 were differentially expressed in CAVS. Ten had a gradient of expression between severity levels and were central in a protein-protein interaction network, most of which were involved in extracellular matrix regulation or inflammation. Among the aortic valve-specific genes, four of the corresponding proteins had a significantly different plasma level in individuals with CAVS. These findings represent a robust foundation for the development of specific biomarkers and therapies for CAVS.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100448"},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12148664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ERBB2 c.1795C>T, p.Arg599Cys variant is associated with left ventricular outflow tract obstruction defects in humans.","authors":"Minna Ampuja, Sabina Ericsson, Ilkka Paatero, Iftekhar Chowdhury, Jenna Villman, Martin Broberg, Amanda Ramste, Diego Balboa, Tiina Ojala, Jessica X Chong, Michael J Bamshad, James R Priest, Markku Varjosalo, Riikka Kivelä, Emmi Helle","doi":"10.1016/j.xhgg.2025.100446","DOIUrl":"10.1016/j.xhgg.2025.100446","url":null,"abstract":"<p><p>Non-syndromic congenital heart defects (CHDs) are occasionally familial and left ventricular outflow tract obstruction (LVOTO) defects are among the subtypes with the highest hereditability. The aim of this study was to evaluate the pathogenicity of a heterozygous ERBB2 variant c.1795C>T, p.Arg599Cys identified in three families with LVOTO defects. Variant detection was done with exome sequencing. Western blotting, digital PCR, mass spectrometry (MS), MS microscopy, and flow cytometry were used to study the function of the ERBB2 variant c.1795C>T. Cardiac structure and function were studied in zebrafish embryos expressing human ERBB2 wild type or c.1795C>T. Proband-derived human induced pluripotent stem cell cardiomyocytes (hiPS-CMs) and endothelial cells (hiPS-ECs) were used for transcriptomic analyses. While phosphorylation of the ERBB2 p.Arg599Cys receptor was not altered, the variant affected dramatically the binding partners of the protein, indicating mislocalization of the mutant ERBB2 from plasma membrane to endoplasmic reticulum. Expression of human ERBB2 p.Arg599Cys in zebrafish embryos resulted in cardiomyocyte hypertrophy, increased cardiac wall thickness, and impaired fractional shortening. Transcriptomic analyses of hiPS-ECs and hiPS-CMs from an individual with the c.1795C>T variant showed aberrant expression of genes related to cardiovascular system development and abnormal response to oxidative stress in both cell types. In conclusion, the heterozygous variant ERBB2 c.1795C>T, p.Arg599Cys leads to abnormal cellular localization of the ERBB2 receptor and induces structural changes and dysfunction in the zebrafish embryo heart. This evidence expands previous findings from animal studies to humans and suggests variants in ERBB2 may be associated with CHD.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100446"},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic germline variants in small cell lung cancer: A systematic review and meta-analysis.","authors":"Sami Ul Haq, Aleem Aamir, Chloe Mighton, Katrina Hueniken, Vivek Philip, Raymond H Kim, Geoffrey Liu, Peter Sabatini, Scott V Bratman, Benjamin H Lok","doi":"10.1016/j.xhgg.2025.100445","DOIUrl":"10.1016/j.xhgg.2025.100445","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100445"},"PeriodicalIF":3.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypertension increases PPV for polycystic kidney disease in PKD1 and PKD2 variant carriers.","authors":"Natalie Telis, Lisa McEwen, Alexandre Bolze, Joshua H Lipschutz, Leon W Sweer, Daniel P Judge, Pamala A Pawloski, Joseph J Grzymski, Catherine Hajek, Kelly M Schiabor Barrett, Nicole L Washington, Elizabeth T Cirulli","doi":"10.1016/j.xhgg.2025.100444","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100444","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic form of KD. Although rare causal variants in the PKD1 and PKD2 genes have been identified, their penetrance and the disease progression and outcome are known to vary, and treatment efficacy in these carriers lags compared to patients with other forms of chronic KD (CKD). To develop a population screening strategy with high sensitivity to individuals likely to develop disease, we characterize the presentation and progression of ADPKD in variant carriers, identified in a multi-center all-comers cohort, as well as the UK Biobank. We show that the positive predictive value of hypertension for future diagnosis of KD is extremely high: 74% and 66% for PKD1 and PKD2, respectively. It is also highly preemptive, with hypertension occurring an average of 11 years before a KD diagnosis. Using pre-disease time point measurements of kidney function prior to their ADPKD diagnosis, we find that PKD1 and PKD2 variant carriers show significantly decreased kidney function (EGFR) an average of 5 years before their clinical diagnosis. Unlike other CKD patients, 54% of variant carriers with hypertension meet the diagnostic threshold for CKD years prior to their disease diagnosis, and their EGFRs are statistically indistinguishable from variant carriers who have already been diagnosed. These findings suggest that a population screening strategy using a combination of targeted sequencing and routine monitoring could identify cases of ADPKD with high sensitivity and support initiating treatment years prior to the current standard of care.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100444"},"PeriodicalIF":3.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A variant in RNF212B may contribute to female infertility and recurrent pregnancy loss.","authors":"Michelle E Darko, Michelle Kappy, Daniel Rabizadeh, Chaim Jalas, Eric J Forman, Paula Brady, Zev Williams","doi":"10.1016/j.xhgg.2025.100443","DOIUrl":"10.1016/j.xhgg.2025.100443","url":null,"abstract":"<p><p>Women with genetic causes of infertility are more likely to experience recurrent pregnancy loss (RPL). Advances in whole-genome sequencing (WGS) have allowed for the improved detection of such genes. One reproductively young patient with a history of RPL underwent 5 in vitro fertilization cycles with nearly complete arrest of blastocyst development and ubiquitous aneuploidy of maternal origin in arrested embryos. Here, we present the discovery of a gene variant, RNF212B, as a potential genetic cause of female infertility and RPL. DNA was extracted and submitted for WGS. After filtering out variants with Genome Aggregation Database allele frequencies exceeding 0.25%, we identified 87 unique variants and conducted a literature search to identify potential associations with infertility. PGT-A analysis of arrested embryos revealed extensive aneuploidies affecting many chromosomes in all embryos. Maternal WGS revealed a homozygous stop-gain mutation in the RNF212B gene. RNF212 has been shown to interact with proteins involved in meiotic recombination, including DMC1 and DNA repair protein RAD51. This homozygous nonsense mutation in the RNF212B gene may be responsible for the presence of aberrant oogonium and for disrupting the meiotic recombination process, thereby contributing to female infertility and RPL.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100443"},"PeriodicalIF":3.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted long-read cDNA sequencing reveals novel splice-altering pathogenic variants causing retinal dystrophies.","authors":"Dalila Capasso, Roberta Zeuli, Gavin Arno, Michael Kwint, Raoul Timmermans, Karla A Ruiz-Ceja, Marianthi Karali, Francesca Simonelli, Sabrina Signorini, Enza Maria Valente, Frans P M Cremers, Sandro Banfi, Susanne Roosing, Daan M Panneman, Suzanne E de Bruijn","doi":"10.1016/j.xhgg.2025.100442","DOIUrl":"10.1016/j.xhgg.2025.100442","url":null,"abstract":"<p><p>Splice-altering variants are suggested to be responsible for part of the missing heritability of inherited retinal diseases (IRDs). The interpretation of these variants is challenging as functional evidence is required to validate pathogenicity. We explored the diagnostic value of a targeted long-read cDNA sequencing (lrcDNA-seq) approach to investigate IRD-associated splicing defects. For each affected individual, RNA was isolated from blood, and for each candidate gene, cDNA amplicons, spanning the complete open reading frame or multiple exons, were generated and subjected to long-read sequencing. We validated our approach by assessing previously described pathogenic splice-altering variants in IRD-associated genes. Next, we investigated six genetically unexplained affected individuals, each carrying pathogenic variant(s) in NMNAT1. In two probands, we provided functional validation for previously identified variants of uncertain significance present on the second allele. In four other subjects, lrcDNA-seq revealed the partial inclusion of an SVA_F retrotransposon in the NMNAT1 mRNA, predicted to introduce a premature stop codon. We showed that targeted lrcDNA-seq is effective in characterizing splice defects and in identifying novel splice-altering variants and uncovered the IRD genetic basis for six previously unexplained subjects. We believe that the implementation of this technique has the potential to contribute to an increased diagnostic rate of IRDs.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100442"},"PeriodicalIF":3.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12099450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coupling deep phenotypic quantification with next-generation phenotyping for 192 individuals with germline histonopathies.","authors":"Emily E Lubin, Elizabeth M Gonzalez, Annabel K Sangree, Emily L Durham, Hannah Klinkhammer, Jing-Mei Li, Sarina M Smith, Dana E Layo-Carris, Kelly J Clark, Ashley J Melendez-Perez, Xiao Min Wang, Rajesh Angireddy, Erin E Weiss, Tahsin Stefan Barakat, Sandra Mercier, Benjamin Cogné, Saskia Koene, Yvonne Hilhorst-Hofstee, Malgorzata Rydzanicz, Rafal Ploski, María de Los Ángeles Gómez Cano, María Palomares-Bralo, Tania Barragán Arévalo, Tiong Yang Tan, Lyndon Gallacher, Suzanne P MacFarland, Rebecca C Ahrens-Nicklas, Tomoki T Nomakuchi, Elizabeth J K Bhoj","doi":"10.1016/j.xhgg.2025.100440","DOIUrl":"10.1016/j.xhgg.2025.100440","url":null,"abstract":"<p><p>Mendelian histonopathies are rare neurodevelopmental disorders (NDDs) caused by germline variants in histone-encoding genes. Here, we perform a more expansive pan-histonopathy interrogation than previously possible. We analyze data from 192 individuals affected by histonopathies. This analysis includes representation of the 185 published individuals with HIST1H1E syndrome, Bryant-Li-Bhoj syndrome, and Tessadori-Bicknell-van Haaften NDD; as well as from seven unpublished individuals, five of whom harbor variants in genes not previously associated with disease (HIST1H2AL/H2AC16, H2AFZ/H2AZ1, HIST1H3D/H3C4, and HIST3H3/H3-4). By intersecting clinician-reported phenotypic data with next-generation phenotyping of published 2D facial photographs (n = 98), we sought to address the lack of established craniofacial gestalts or characteristic phenotypic patterns for this community. While these analyses may suggest a histone core versus linker protein basis of delineation, they more strikingly highlight data gaps that confound the identification of phenotypic patterns at this time. Based on this, we developed an updated standardized clinical survey, which allowed us to identify the second known individual with a germline histonopathy and a cancer diagnosis. Notably, the community-wide cancer incidence is currently 1%, which falls below the recommended 5% cut off for routine surveillance. Ultimately, this work highlights the ways in which histonopathy-associated phenotypes change throughout the lifespan, necessitating longitudinal re-evaluation; that every identified individual shapes our understanding of these syndromes in a way that improves care for this community; and the value of ongoing translational work to address the outstanding question of cancer predisposition for individuals living with germline histonopathies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100440"},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.","authors":"Sarah L Stenton, Kristen Laricchia, Nicole J Lake, Sushma Chaluvadi, Vijay Ganesh, Stephanie DiTroia, Ikeoluwa Osei-Owusu, Lynn Pais, Emily O'Heir, Christina Austin-Tse, Melanie O'Leary, Mayada Abu Shanap, Chelsea Barrows, Seth Berger, Carsten G Bönnemann, Kinga M Bujakowska, Dean R Campagna, Alison G Compton, Sandra Donkervoort, Mark D Fleming, Lyndon Gallacher, Joseph G Gleeson, Goknur Haliloglu, Eric A Pierce, Emily M Place, Vijay G Sankaran, Akiko Shimamura, Zornitza Stark, Tiong Yang Tan, David R Thorburn, Susan M White, Maha S Zaki, Eric Vilain, Monkol Lek, Heidi L Rehm, Anne O'Donnell-Luria","doi":"10.1016/j.xhgg.2025.100441","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100441","url":null,"abstract":"<p><p>Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed [84%]) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, as well as other rare disease cohorts. Using dedicated pipelines to address the technical challenges posed by the mtDNA-circular genome, variant heteroplasmy, and nuclear misalignment-we called single nucleotide variants, small insertions/deletions, and large mtDNA deletions from exome and/or genome sequencing data, in addition to RNA sequencing data when available. Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (1 large deletion, 8 reported pathogenic variants, and 1 previously unreported likely pathogenic variant), as well as candidate diagnostic variants in a further 11 undiagnosed families. In one additional undiagnosed proband, detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair. Overall, mtDNA variant calling from data generated by exome and genome sequencing-primarily for nuclear variant analysis-resulted in a genetic diagnosis for 0.2% of undiagnosed families affected by a broad range of rare diseases, as well as the identification of additional promising candidates in 0.2%.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100441"},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}