American journal of human genetics最新文献

{"title":"Sensitivity of HiFi long-read genome sequencing for difficult-to-detect pathogenic variants when applied to real-world clinical laboratory samples.","authors":"Joseph M Devaney,Jessica X Chong,Patricia C Lopes,Jessica Noya,April S Berlyoung,Shamila Yusuff,Solomon Lynch,Rhonda Brandon,Kathleen S Hruska,Lucas Lochovsky,Julianna Spangler,Kirsty McWalter,Keith Nykamp,Sarah R Poll,Andrew B Stergachis,John Greally,Paul Kruszka,Egor Dolzhenko,Xiao Chen,Alexander V Robertson,William J Rowell,Juniper A Lake,Andrew Carroll,Robert Kueffner,Michael A Eberle,Flavia M Facio,Michael J Bamshad,Britt Johnson","doi":"10.1016/j.ajhg.2026.04.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.04.001","url":null,"abstract":"Leveraging new sequencing and omic technologies to enhance the detection of pathogenic variants in known disease genes is a key step toward increasing the likelihood of a precise genetic diagnosis for affected individuals. Short-read sequencing is widely used in clinical laboratories for multi-gene panels and exome and genome sequencing, but this technology has inherent limitations in detecting certain classes of genetic variation. As a result, diagnostic laboratories continue to offer complementary assays, often used sequentially, reducing efficiency and speed in providing a diagnosis. We applied PacBio long-read genome sequencing (HiFi) to samples from 191 probands previously tested with short-read sequencing alone and/or other diagnostic technologies and enriched for pathogenic variants difficult to detect (VDDs). HiFi's pipeline automatically detected 479 of 481 (99.6%) disease-causing variants, many of which were called in samples not optimized for long-read genome sequencing (such as buccal samples or low-molecular-weight DNA). The two variants not automatically detected were a mosaic trisomy 18 (23% mosaicism) and a 5,594-bp mosaic deletion (13% mosaicism). However, other mosaic variants were detected, indicating that HiFi at ∼30× genome coverage is sensitive to the degree of mosaicism. Of 481 variants, 49 were suspected based on the clinical report but not confirmed molecularly prior to HiFi. Our findings demonstrate that HiFi sequencing detects a wide range of VDDs in real-world clinical laboratory samples, highlighting a key advantage of HiFi as a potential first-tier test over the myriad of complementary technologies currently used to detect VDDs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"4 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benchmarking genetic birth prevalence estimates against newborn screening data.","authors":"Michael C Sierant,Nicholas Knoblauch,Evan Witt,Daniel Gaffney,Sara L Pulit,Arthur Wuster","doi":"10.1016/j.ajhg.2026.04.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.04.002","url":null,"abstract":"Accurate prevalence estimates for rare congenital conditions are critical for understanding disease epidemiology and enabling drug development. They inform public health investment, identify communities with high disease burden or underdiagnosis, and highlight unmet clinical need. Large biobanks have enabled genetics-based models to estimate disease prevalence. Autosomal-recessive (AR) diseases are particularly suited to this approach, as birth prevalence can be inferred from pathogenic allele frequency in unaffected populations; however, this approach has not been validated against real-world clinical datasets at scale. Newborn screening (NBS), which tests for neonatal diseases using quantitative diagnostic methods, provides a uniquely robust comparator for birth prevalence with low ascertainment bias, large sample size, and low diagnostic variability. With the objective of benchmarking a commonly used approach for determining disease prevalence, we applied a genetic model to estimate birth prevalence for 28 AR diseases from NBS panels and compared them with reported birth prevalence from 23 million newborns in the United States. We found that concordance between the genetic estimate and NBS was impacted by the source of allele frequency estimates, ancestry-matching methodology, and pathogenic variant inclusion criteria. Incorporating these refinements, we demonstrate that a genetics-first approach can provide first-order estimates of AR disease birth prevalence for 25 of 28 NBS diseases (89%). However, we note a general underestimate of the genetic prevalence, suggesting that identifying additional sources of pathogenicity would improve concordance with NBS. Further, we assessed the impact of epidemiological and genetic variables, highlighting diseases where genetic prevalence estimates may not be accurate.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"136 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147743876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining a tandem repeat catalog and variation clusters for genome-wide analyses and population databases.","authors":"Ben Weisburd,Egor Dolzhenko,Mark F Bennett,Matt C Danzi,Isaac R L Xu,Hope Tanudisastro,Bida Gu,Adam English,Laurel Hiatt,Tom Mokveld,Guilherme De Sena Brandine,Readman Chiu,Nehir Edibe Kurtas,Helyaneh Ziaei Jam,Harrison Brand,Indhu-Shree Rajan-Babu,Melanie Bahlo,Mark J P Chaisson,Stephan Züchner,Melissa Gymrek,Harriet Dashnow,Michael A Eberle,Heidi L Rehm","doi":"10.1016/j.ajhg.2026.03.020","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.020","url":null,"abstract":"Tandem repeat (TR) catalogs are important components of repeat genotyping studies because they define the genomic coordinates and expected motifs of all TR loci being analyzed. In recent years, genome-wide studies have used catalogs ranging in size from fewer than 200,000 to over 7 million loci. These catalogs differed not only in which loci were included but often also in their definitions of TR locus boundaries and motifs. Now, with multiple groups developing public databases of TR variation in large population cohorts, there is a risk that the use of divergent repeat catalogs will lead to confusion, fragmentation, and incompatibility across resources. Here, we compare existing TR catalogs and discuss desirable features of a comprehensive genome-wide catalog. We then present a new, richly annotated catalog designed for genome-wide analyses and population datasets based on short-read or long-read samples. Additionally, using an algorithm that leverages long-read HiFi sequencing data, our catalog stratifies TRs into (1) isolated repeats suitable for repeat copy-number analysis and (2) variation clusters where TRs are embedded within wider polymorphic regions best studied through sequence-level analysis. We share the TR catalog, variation clusters, and annotations through the TRExplorer portal in order to support both the initial selection of TR loci for inclusion in an analysis and the subsequent interpretation of results.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"18 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147735341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A flexible and unified framework for single- and multi-outcome Mendelian randomization using summary statistics.","authors":"Bowei Kang,David Li,Ke Xu,Jianhai Chen,Sihao Feng,Jinyu Wang,Guimin Gao,Shinya Tasaki,Brandon L Pierce,David A Bennett,Lin S Chen","doi":"10.1016/j.ajhg.2026.03.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.017","url":null,"abstract":"Mendelian randomization (MR) is widely used to evaluate causal effects of complex trait exposures on disease outcomes. Recently, MR has been increasingly applied to molecular traits, such as gene expression, to map risk genes. However, transcriptome-wide MR (TWMR) faces unique challenges. The number of available cis-QTLs as instrumental variables (IVs) is often limited, and horizontal pleiotropy is pervasive, violating core MR assumptions and compromising inference validity. We introduce FusioMR, a robust MR framework tailored for molecular trait exposures while also applicable to complex trait exposures. Our single-outcome model, FusioMRs, incorporates gene-region-specific empirical priors informed by the number and strength of QTLs, linkage disequilibrium, and effect size consistency. It uses sampling-based inference to improve robustness when instruments are limited. Our multi-outcome model, FusioMRm, is motivated by the observation that many complex diseases have correlated diseases, subtypes, or comorbidities, which could be affected by shared or correlated exposures. FusioMRm jointly analyzes two correlated outcomes, leveraging shared IVs and pleiotropic effects of shared/correlated exposures to improve estimation precision and power, particularly for underpowered outcomes. We applied FusioMRs to identify cell-type-specific gene expression traits associated with Alzheimer disease using single-cell eQTL and GWAS summary data. We applied FusioMRm to detect alternative polyadenylation events affecting atrial fibrillation and ischemic stroke, and to estimate the causal effect of low-density lipoprotein on ischemic stroke in South Asian populations by borrowing information from European ancestry data. These applications highlight the generalizability of FusioMR for both molecular and complex trait exposures.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"186 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of LFSPRO prediction in TP53 mutation status for prospectively collected probands.","authors":"Jessica L Corredor,Ruonan Li,Elissa B Dodd-Eaton,Jacynda Casey,Ashley H Woodson,Nam H Nguyen,Gang Peng,Angelica M Gutierrez,Banu K Arun,Wenyi Wang","doi":"10.1016/j.ajhg.2026.03.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.014","url":null,"abstract":"Genetic counseling and testing for germline mutations are essential for identifying individuals at increased risk for cancer. Pathogenic/likely pathogenic (P/LP) variants in TP53 are diagnostic of Li-Fraumeni syndrome (LFS), a highly penetrant disorder with diverse, early-onset tumors. Current clinical guidelines, such as Chompret and classic criteria, provide frameworks for identifying individuals at risk for P/LP TP53 variants; however, genetic counselors often encounter people with features concerning for LFS that do not clearly meet established criteria, creating challenges for risk assessment and testing decisions. We evaluated whether LFSPRO, a Mendelian, family-history-based model that estimates the individual's probability of harboring a deleterious TP53 variant, improves identification of individuals with LFS relative to guideline criteria. In a prospectively collected cohort of 178 probands who underwent clinical genetic counseling and germline TP53 testing, LFSPRO showed superior discrimination compared with Chompret criteria, with higher sensitivity (81% vs. 33%) and specificity (88% vs. 65%) and improved positive predictive values (PPVs: 0.53 vs. 0.14; negative predictive values [NPVs]: 0.96 vs. 0.85). Receiver operating characteristic analysis confirmed strong discriminatory performance (area under the curve [AUC] = 0.88). Calibration analysis using observed-to-expected ratios indicated good agreement between predicted and observed P/LP variant frequencies (observed/expected = 1.07). These findings demonstrate that LFSPRO outperforms traditional guideline-based criteria for identifying individuals with TP53 mutations in real-world clinical settings. By providing quantitative, well-calibrated TP53 P/LP variant probabilities rather than binary classifications, LFSPRO can enhance genetic counseling and support testing decisions, particularly for individuals who do not clearly meet existing criteria.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"17 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PACells identifies phenotype-associated cell states from single-cell chromatin accessibility profiles.","authors":"Jiao Hua,Qiongyu Sheng,Shutong Xiao,Yang Zhou,Jing Qi,Shuilin Jin","doi":"10.1016/j.ajhg.2026.03.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.012","url":null,"abstract":"Identifying cell states that drive clinical phenotypes is crucial for dissecting regulatory landscapes, pathogenesis, and targeted therapies of disease in single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq). Here, we present PACells, a framework that links clinical phenotypes from bulk ATAC-seq data with individual cells from scATAC-seq data to identify critical cell states at single-cell resolution. PACells outperforms other methods in predicting cells and molecular signatures associated with disease and gene mutation. PACells discerns clinical cell states and regulatory elements relevant to Alzheimer disease (AD) and poor survival in glioblastoma. Further, PACells is extended to transcriptomics for melanoma datasets with immunotherapy outcomes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"49 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147655832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating genetic data with biological insight: A practical guide to cis-Mendelian randomization.","authors":"Ville Karhunen,Benjamin Woolf,Pallav Bhatnagar,Dipender Gill,Stephen Burgess","doi":"10.1016/j.ajhg.2026.03.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.011","url":null,"abstract":"Cis-Mendelian randomization is a computational approach that uses genetic variants from a biologically relevant gene region to assess the plausibility of a causal effect of a specific mechanism on an outcome of interest. As the use of cis-Mendelian randomization has recently increased due to the abundance of genetic association data for molecular quantitative traits, there is a need for informed guidance on how best to conduct such studies. Here, we review and discuss the key considerations for conducting robust cis-Mendelian randomization analyses. The main considerations include selection of the gene region of interest, the choice of the best traits to proxy the exposure of interest, variant selection and validation, and relevant sensitivity analyses. We highlight the importance of incorporating biological insight throughout the whole analysis process and that the analytical methods should be tailored to each gene region. Moreover, we point out some key differences from genome-wide Mendelian randomization-where variants are selected across the genome-and emphasize that cis-Mendelian randomization requires a distinct set of sensitivity analyses. We believe the advice we provide in this review will lead to a higher standard in planning, conducting, reviewing, and interpreting cis-Mendelian randomization studies.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"61 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147655961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism.","authors":"Debora Tibbe,Marie Ronja Vogt,Tess Holling,Lea Dewi Schlieben,Fanny Kortüm,Moneef Shoukier,Christoph Bagowski,Felix Distelmaier,Luisa Averdunk,Alexej Knaus,Peter Krawitz,Alma Kuechler,Elke Lainka,Amelie Stalke,Sandra von Hardenberg,Bernd Auber,Eva-Doreen Pfister,Bruno Reversade,Anthony Sabbagh,Aida M Bertoli-Avella,Salem Alawbathani,Elizabeth E Palmer,Manisha Chauhan,Rocio Rius,Yoonji Kim, ,Dzhoy Papingi,Deborah Bartholdi,Dominique Braun,Oliver Maier,April Dinwiddie,Elisabeth Steichen-Gersdorf,Andreas R Janecke,Anatoly Tiulpakov,Nikolay Zernov,Maria Izabel Arismendi,Alexander A L Jorge,Himanshu Goel,Lauren Dreyer,Lily Loughman,Holger Prokisch,Kerstin Borgmann,Kerstin Kutsche","doi":"10.1016/j.ajhg.2026.03.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.010","url":null,"abstract":"DNA replication is carried out by the replisome and is essential for maintaining genome integrity and cell proliferation. Pathogenic variants in genes encoding various replisome components cause microcephalic primordial dwarfism (MPD), characterized by growth retardation, microcephaly, and developmental abnormalities. Here, we report bi-allelic hypomorphic variants in WDHD1 as a cause of MPD with a broad spectrum of additional abnormalities, including acute liver failure, in 17 subjects from 14 families. WDHD1 encodes a replisome scaffolding protein (also known as AND-1 and Ctf4), which is essential for replisome assembly, replication fork stability, and sister chromatid cohesion. We found aberrant splicing of WDHD1 pre-mRNAs for all intronic variants tested and markedly reduced WDHD1 protein levels in subject-derived fibroblasts. Fibroblasts with bi-allelic WDHD1 variants showed globally reduced replication fork speed and impaired replication control, accompanied by spontaneous DNA damage and a G1-to-S transition defect. Using various cell biology approaches, we show that subject fibroblasts displayed reduced proliferation, abnormal nuclear morphology, including micronuclei, multilobed, and enlarged nuclei, as well as an increased number of metaphases with premature sister chromatid separation. Together, our findings establish WDHD1 as a protein required for normal organismal growth and development in humans and underscore its multiple functions in maintaining genome integrity.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"123 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147648874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measuring disease likelihood in genomic ascertainment","authors":"Julie C. Sapp, Katie L. Lewis, Emily W. Modlin, Alana Davidson, Charlotte Linton Early, Adam H. Buchanan, Alexis Darling, Jacquelyn Mahder, Cara Z. McCormick, Allison J. de Moya, Brooke Rosenblum, Morgan Similuk, Kelly Tangney, Meghan C. Towne, Clesson Turner, Caralynn M. Wilczewski, Jennifer J. Johnston, Leslie G. Biesecker","doi":"10.1016/j.ajhg.2026.03.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.03.009","url":null,"abstract":"Understanding the yield, predictive power, and utility of a secondary finding is critical for policy development and can help inform discussions for population screening. Because American College of Medical Genetics and Genomics (ACMG) Secondary Findings guidelines are applied in diverse testing contexts, we recruited participants from multiple sources to address these questions. We assessed our first 1,500 inquiries to review the disorders/genes that were returned to these individuals. After eligibility screening, we enrolled 227 recipients and completed genotyping, cascade testing, and phenotyping efforts for 163 probands. From evaluating these families, it became clear that there were highly variable outcomes for the diagnostic yield of secondary findings. To objectively and quantitatively assess this, we developed a method to measure the likelihood that the family was, in fact, affected with the disorder associated with the secondary finding variant. We assessed this in detail for 59 families who had a secondary finding of <ce:italic>BRCA1</ce:italic>- or <ce:italic>BRCA2</ce:italic>-related cancer predisposition. Our estimates of the likelihood of a valid clinicomolecular diagnosis ranged from 26.2% to 100%. Over half (51%) of the families met criteria for diagnostic testing, indicating that diagnostic testing for these disorders is underused and that secondary findings testing is being applied inappropriately to these families. These results will be useful for policy refinement for secondary findings and are also relevant to considerations of population genomic screening.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"63 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank","authors":"Ioanna K. Katzourou, LINC consortium, Marianne B.M. van den Bree, George Kirov, Michael J. Owen, James T.R. Walters, Peter A. Holmans, Jane Lynch, Ioanna K. Katzourou, Jack F.J. Underwood, David A. van Heel, Sarah Finer, Daniel Stow, Golam M. Khandaker, Nicholas J. Timpson, John A.A. MacLeod, Julie P. Clayton, Ruby S.M. Tsang, Jane Sprackman, Shahid Khan, Inês Barroso, Rupert A. Payne, Mark Mon-Williams, Megan L. Wood, Nabila Ali, Hilary C. Martin, Thomas Werge, Andrés Ingason, Morteza Vaez, Lam O. Huang, Inês Barroso, Julie Clayton, Golam Khandaker, Daniel Stow, Nicolas Timpson, Ruby Tsang, Jack Underwood, Megan Wood, George Kirov, James Walters, Michael J. Owen, Peter Holmans, Marianne B.M. van den Bree","doi":"10.1016/j.ajhg.2026.02.021","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.02.021","url":null,"abstract":"Internalizing and cardiometabolic multimorbidity (ICM-MM) represents a major clinical challenge, negatively impacting life expectancy and quality of life and resulting in considerable healthcare costs. Individuals with a copy-number variant associated with increased risk of neurodevelopmental conditions (ND-CNV) are more likely to develop mental or physical ill health; however, the effects on ICM-MM remain poorly understood. We used data from the UK Biobank (ND-CNV <ce:italic>N</ce:italic> = 7,549, 1.62%) to examine the effect of ND-CNVs on ICM-MM. ICM-MM was defined as a combination of any internalizing condition (depression, anxiety, or somatic symptom disorder) with each of five cardiometabolic conditions (hypertension, dyslipidemia, obesity, type 2 diabetes (T2D), and chronic kidney disease). We also studied whether ICM-MM risk in those with ND-CNVs differed by sex or presence of a deletion versus a duplication. We established associations between dosage-sensitive genes within ND-CNVs and ICM-MM and explored the interaction between the presence of ND-CNVs and polygenic risk scores (PRSs) of internalizing and cardiometabolic traits on ICM-MM risk. The presence of ND-CNVs was associated with ICM-MM (odds ratio [OR] range: 1.21–1.57). Female participants with ND-CNVs were more likely to have any internalizing condition and T2D, and those with a deletion were more likely to have any internalizing condition and obesity. The number of deleted haploinsufficient genes, but not duplicated triplosensitive genes, was associated with ICM-MM. No interactions between ND-CNVs and PRSs were found. We find that ND-CNVs increase the likelihood of ICM-MM, with evidence of sex differences and stronger effects for deletions. Increased clinical awareness can help ameliorate this risk.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"15 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}