HGG Advances最新文献

{"title":"A homozygous variant in cardiac troponin I3, TNNI3, causes severe pediatric restrictive cardiomyopathy.","authors":"Jirko Kühnisch, Cara L Barnett, Josephine Brendel, Lara Berklite, Chet Villa, Wenke Seifert, Sabine Klaassen, Karin Klingel, K Nicole Weaver","doi":"10.1016/j.xhgg.2026.100598","DOIUrl":"10.1016/j.xhgg.2026.100598","url":null,"abstract":"<p><p>Dilated cardiomyopathy (DCM) results from systolic dysfunction, while restrictive cardiomyopathy (RCM) is due to diastolic dysfunction. The diverse pathophysiology of primary DCM and RCM suggests distinct underlying genetic mechanisms. A well-established disease gene for DCM and RCM is cardiac troponin I3 (TNNI3), which causes dominant and recessively inherited forms. In children, bi-allelic truncating TNNI3 variants have typically been associated with DCM, and heterozygous missense TNNI3 variants are associated with RCM. We report a 2-year-old female with severe RCM that is genetically caused by a homozygous TNNI3 nonsense variant, c.406C>T (p.Arg136∗), which results in a more distal (C-terminal) truncation than most previously reported disease-associated nonsense variants. In myocardial biopsies of the patient, TNNI3 protein abundance was diminished, suggesting that residual TNNI3 function may underlie RCM, while TNNI3 absence causes DCM. The RCM in this patient was treatment refractory and resulted in a heart transplant at the age of 28 months. Overall, recessive TNNI3 protein truncation causes severe pediatric RCM, suggesting that the allelic status, type of genetic alteration, and length of TNNI3 protein truncation determine cardiomyopathy onset and subtype manifestation.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100598"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595237","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":"\"I make my own decisions\": Views on precision medicine research participation decisions from adults with intellectual disability.","authors":"Katherine E McDonald, Eulena Banzer, Mark Cooley, Rijul Singhal, Tawara D Goode, Krzysztof Kiryluk, Maya Sabatello","doi":"10.1016/j.xhgg.2026.100589","DOIUrl":"10.1016/j.xhgg.2026.100589","url":null,"abstract":"<p><p>Autonomy is a leading indicator of well-being and a cornerstone principal of research ethics. Yet adults with intellectual disability are routinely denied autonomy in research settings, affecting participation and generalizability. To inform health research policy and practice, we conducted a national survey of 150 adults with intellectual disability to explore their views on autonomy and decision-making in precision medicine research (PMR), a leading area of health research. Participants expressed strong interest in participating in PMR and controlling their participation decisions, sometimes with support. Findings highlight the need for policies and practices that honor these interests and facilitate autonomy. Over time, such efforts can improve health outcomes for this underserved population.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100589"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13091285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436322","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":"Rare type I collagen variants in early-onset bicuspid aortic valve disease: Overlap with Ehlers-Danlos syndrome and osteogenesis imperfecta.","authors":"Sara Mansoorshahi, Catherina Tovar Pensa, Erin Carter, Anna Sabate-Rotes, Hector I Michelena, Anji T Yetman, Julie De Backer, Laura Muiño Mosquera, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S Hui, Anthony Caffarelli, Yuli Y Kim, Rodolfo Citro, Margot De Marco, Justin T Tretter, Kim L McBride, Simon C Body, Cathleen Raggio, Dianna M Milewicz, Siddharth K Prakash","doi":"10.1016/j.xhgg.2026.100627","DOIUrl":"10.1016/j.xhgg.2026.100627","url":null,"abstract":"<p><p>Bicuspid aortic valve (BAV) is the most common congenital heart lesion in adults and is often associated with thoracic aortic aneurysms and aortic stenosis. The genetic causes of most non-syndromic cases of BAV remain unknown. Pathogenic variants in COL1A1 or COL1A2, which encode type I collagen (COL1), cause osteogenesis imperfecta (OI), a rare disorder marked by bone fragility. Although aortic valve phenotypes, including BAV, have been described in OI, COL1 genes have not been implicated in sporadic BAV. We report rare COL1 variants in individuals with early-onset BAV (EBAV) complications. Whole-exome sequencing was performed in 272 non-syndromic BAV probands who developed valve or aortic complications before age 30 (EBAV) and 272 biological relatives. Variants were filtered by allele frequency, inheritance pattern, ClinVar classification, and in silico predictions. Participants with rare predicted damaging COL1 variants were recontacted to confirm phenotypes. Rare coding variants in COL1A1 (n = 5) and COL1A2 (n = 5) were identified in 10 (4%) EBAV probands, representing a 30-fold enrichment compared with European ancestry populations. Only two variants involved glycine substitutions in triple-helical domains. Affected probands presented with aortic regurgitation and/or thoracic aneurysms requiring repair and exhibited subtle connective tissue features such as joint hypermobility, recurrent fractures, or dental abnormalities. Predicted damaging COL1 variants are enriched in EBAV probands with features overlapping OI and Ehlers-Danlos syndrome, though involving different residues than those in OI. Genetic testing for these variants may help identify individuals who could benefit from personalized surveillance or targeted preventive strategies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100627"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13273786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975918","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":"Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.","authors":"Nikki D Russell, Jonathan M Downie, Mark B Bromberg, Stefan M Pulst, Lynn B Jorde","doi":"10.1016/j.xhgg.2026.100614","DOIUrl":"10.1016/j.xhgg.2026.100614","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and whole-exome sequencing data from 1,034 individuals with ALS were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA (mtDNA) polymerase, emerged as a top candidate gene. RNA sequencing (RNA-seq) analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways, including translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected control subjects. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mtDNA maintenance. Additionally, POLG variant carriers had elevated mtDNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mtDNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to the ALS etiology.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100614"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147663478","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":"Genetic architecture of 67 oral diseases and their links to systemic diseases.","authors":"Kirika Karppinen, Hanna M Ollila, Kanwal Batool, Erik Abner, David P Rice, Aarno Palotie, Tuula Palotie, Samuli Ripatti, Nina Mars, Satu Strausz","doi":"10.1016/j.xhgg.2026.100633","DOIUrl":"10.1016/j.xhgg.2026.100633","url":null,"abstract":"<p><p>Oral and craniofacial diseases are common, yet their genetic basis and links to systemic health are incompletely understood. We performed genome-wide association analyses of 67 oral phenotypes in 500,348 FinnGen participants, identifying 102 genome-wide significant loci, including 45 previously unreported associations. 48 loci remained significant after category-level Bonferroni correction. Fine-mapping revealed 14 coding variants, such as a missense variant in USP31 for caries and in MANBA for oral leukoplakia, and a stop-gained variant in GPNMB for temporomandibular disorders. Human leukocyte antigen (HLA) analyses implicated DQA1 and DQB1 alleles in lichen planus and other mucosal disorders. We observed 378 statistically significant genetic correlations (r_g) among oral traits, such as tooth loss and chronic apical periodontitis (r_g = 0.91, 95% confidence interval [CI]: [0.76, 1.05], p = 1.7 × 10^-34), and 419 significant correlations between oral and systemic diseases, including periodontal diseases with chronic laryngitis (r_g = 0.97, 95% CI: [0.58, 1.36], p = 1.2 × 10^-6) and bruxism with gastroesophageal reflux (r_g = 0.51, 95% CI: [0.38, 0.65], p = 1.1 × 10^-13). These results expand the catalog of oral disease loci, uncover Finnish-enriched risk alleles, and highlight shared inflammatory, immune, and structural pathways connecting oral and systemic health.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100633"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272899","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":"Advancing risk gene discovery across the allele frequency spectrum.","authors":"Madison Caballero, Behrang Mahjani","doi":"10.1016/j.xhgg.2026.100599","DOIUrl":"10.1016/j.xhgg.2026.100599","url":null,"abstract":"<p><p>The discovery of genetic risk factors has transformed human genetics, yet the pace of new gene identification has slowed despite the exponential expansion of sequencing and biobank resources. Current approaches are optimized for the extremes of the allele frequency spectrum: rare, high-penetrance variants identified through burden testing and common, low-effect variants mapped by genome-wide association studies. Between these extremes lie variants of intermediate frequency and effect size for which statistical power is limited, pathogenicity is often misclassified, and gene discovery lags behind empirical evidence of heritable contribution. This \"missing middle\" represents a critical blind spot across disease areas, from neurodevelopmental and psychiatric disorders to cancer and aging. In this review, we organize strategies for risk gene identification by variant frequency class, highlighting methodological strengths and constraints at each scale. We draw on lessons across fields to illustrate how innovations in variant annotation, joint modeling, phenotype refinement, and network-based inference can extend discovery into the intermediate range. By framing the frequency spectrum as a unifying axis, we provide a conceptual map of current capabilities, their limitations, and emerging directions toward more comprehensive risk gene discovery.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100599"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595263","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":"Novel MC1R variants cause red hair and lighter skin color.","authors":"Deepak K Kashyap, Srashti J Agrawal, Meenakshisundaram Karthikeyan, Disha Biradar, Eerapagula Ramesh, Krithika Subramanian, Lomous Kumar, Urgyan Chorol, Audditiya Bandopadhyay, A Vasanthakumar, Nagarjuna Pasupuleti, Tamilselvan Jayavelu, Ajay K Mahato, Periyasamy Govindaraj, Gyaneshwer Chaubey, Bratati Kahali, Vivek T Natarajan, Kumarasamy Thangaraj","doi":"10.1016/j.xhgg.2026.100603","DOIUrl":"10.1016/j.xhgg.2026.100603","url":null,"abstract":"<p><p>The melanocortin 1 receptor (MC1R) is one of the fundamental proteins regulating skin and hair color in mammals. In India, the red hair color (RHC) phenotype is extremely rare. We analyzed MC1R and identified an ultra-rare pathogenic variant, c.872C>A (p.Ala291Asp), that is responsible for the RHC phenotype in an Indian child. Further, we screened the complete coding region of MC1R in a total of 11,021 individuals, representing 91 distinct Indian populations across India, and found a total of 21 novel or ultra-rare variants. In silico, in vitro, and zebrafish-based functional analysis showed that c.742G>T (p.Gly248Cys) and p.Ala291Asp variants lead to loss-of-function (LoF) effects. The distribution of some of these variants differed significantly among Indian populations. One of them is MC1R c.-226A>T (rs3212363), which is significantly associated with lighter skin pigmentation in the Bodh population inhabited in Ladakh. On average, TT homozygotes were 8.46 melanin units lighter compared with AA homozygotes (95% confidence interval [CI]: 3.211 to 13.72; adjusted p = 0.0005). Our study identifies and functionally validates ultra-rare MC1R variants as potential causes of RHC phenotype in Indians.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100603"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623858","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":"When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.","authors":"Jin-Huan Lin, Hao Wu, Xin-Ying Tang, Emmanuelle Masson, Peter D Stenson, Andrew D Phillips, David N Cooper, Claude Férec, Zhuan Liao, Wen-Bin Zou, Jian-Min Chen","doi":"10.1016/j.xhgg.2026.100602","DOIUrl":"10.1016/j.xhgg.2026.100602","url":null,"abstract":"<p><p>Variants with intermediate functional effects-neither fully disruptive nor functionally neutral-represent an under-recognized source of genetic complexity and define a functional gray zone that complicates variant classification. Here, we address this issue using GT>GC (+2T>C) 5' splice-site variants as a tractable model, as approximately 15%-18% of such substitutions retain variable levels of residual wild-type (WT) transcript. Using residual WT transcript as a quantitative functional readout, we first revisited disease-associated GT>GC variants previously shown to retain substantial WT transcript, including SPINK1 c.194+2T>C, HBB c.315+2T>C, and BRCA2 c.8331+2T>C, illustrating how intermediate splicing effects complicate clinical interpretation across distinct genes and disease contexts. We then performed a locus-wide assessment of all 26 theoretically possible GT>GC substitutions in CFTR, integrating SpliceAI delta donor-loss scores with classifications from expert-curated databases. Minigene splicing analyses of four selected CFTR variants, together with full-length and minigene analyses of a BAP1 GT>GC variant with conflicting clinical interpretations, revealed heterogeneous and context-dependent splicing outcomes, underscoring both inter-assay variability and the inherent limitations of commonly used splicing assay systems. Collectively, our findings indicate that GT>GC variants capable of generating appreciable residual WT transcript exemplify a broader class of intermediate-effect alleles that expose the limitations of both computational prediction and experimental assessment. These observations highlight the need for classification frameworks that incorporate quantitative functional data and better capture the continuum of variant effects.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100602"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610239","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":"Broadening the phenotypic and molecular spectrum of PRS deficiency in females.","authors":"Tamara Braid, Sydney Scholten, Sangeetha Yoganathan, Abrar K Alsalamah, Daniel Deschênes, Ghislain Deslongchamps, Sharan Goobie, Elise Heon, Ingrid Tein, Ashish R Deshwar","doi":"10.1016/j.xhgg.2026.100601","DOIUrl":"10.1016/j.xhgg.2026.100601","url":null,"abstract":"<p><p>Phosphoribosylpyrophosphate synthetase (PRS) deficiency is a rare X-linked disorder caused by variants in the PRPS1 gene. While males typically exhibit severe phenotypes, heterozygous females may or may not be affected, most likely explained by skewed X chromosome inactivation and its impact on enzyme activity. In this study, we describe and study both unique and previously described variants in PRPS1 in female patients. We provide detailed molecular and phenotypic information for two pediatric patients who possess unique variants in PRPS1, one of whom presents with bilateral tongue fasciculations, extending the cranial neuropathy spectrum described in these conditions. We summarize and compare published cases of females with PRPS1 deficiency to establish common phenotypic features and demonstrate that all disease-causing variants are missense variants scattered across the protein. In silico modeling was performed for all variants causing PRS deficiency in females to highlight different unique impacts on the protein. Altogether, these findings expand the molecular and phenotypic spectrum of PRS deficiency in females, demonstrate that heterozygous females can manifest significant neurological and sensory impairment early in life, and highlight cranial nerve XII involvement. Continued functional and clinical studies are required to refine genotype-phenotype correlations and inform targeted diagnostic and therapeutic strategies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100601"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610266","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":"Explicitly modeling genetic ancestry to improve polygenic prediction accuracy for height in a large, admixed cohort of US Latinos: Findings from HCHS/SOL.","authors":"Xin Wang, Tamar Sofer, Oleksandr Frei, Robert Kaplan, Krista M Perreira, Nora Franceschini, Humberto Parada, Laura Zhou, Ole A Andreassen, Hector Gonzalez, Anders M Dale, Iris J Broce","doi":"10.1016/j.xhgg.2026.100597","DOIUrl":"10.1016/j.xhgg.2026.100597","url":null,"abstract":"<p><p>Polygenic scores (PGSs) offer moderate to high prediction accuracy for complex traits, but most are developed in European ancestry cohorts, reducing their performance in populations of other ancestries. This study aimed to improve standing height prediction, a heritable and ancestry-influenced trait, in an admixed Latino cohort, the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), by modeling ancestry using principal components (PCs) alongside PGSs. SNPs were selected from a large European ancestry genome-wide association study (GWAS) using various p value thresholds, and weights were trained using traditional and penalized regression in the UK Biobank (UKB). PGSs with PCs were trained separately in the HCHS/SOL and UKB. Compared to PGSs alone, modeling PGSs with PCs moderately improved height prediction in the HCHS/SOL (squared correlation [R²] increase of ∼0.05), while mild improvements were observed in the UKB (R² increase of ∼0.01). These results underscore the importance of incorporating genetic ancestry into predictive models for admixed populations, particularly when the trait exhibits ancestry-specific associations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100597"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13157043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575574","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}