American journal of human genetics最新文献

{"title":"Role of X chromosome and dosage-compensation mechanisms in complex trait genetics.","authors":"Yu Fu, Aino Kenttämies, Sanni Ruotsalainen, Matti Pirinen, Taru Tukiainen","doi":"10.1016/j.ajhg.2025.04.004","DOIUrl":"10.1016/j.ajhg.2025.04.004","url":null,"abstract":"<p><p>The X chromosome (chrX) is often excluded from genome-wide association studies due to its unique biology complicating the analysis and interpretation of genetic data. Consequently, the influence of chrX on human complex traits remains debated. Here, we systematically assessed the relevance of chrX and the effect of its biology on complex traits by analyzing 48 quantitative traits in 343,695 individuals in UK Biobank with replication in 412,181 individuals from FinnGen. We show that, in the general population, chrX contributes to complex trait heritability at a rate of 3% of the autosomal heritability, consistent with the amount of genetic variation observed in chrX. We find that a pronounced male bias in chrX heritability supports the presence of near-complete dosage compensation between sexes through X chromosome inactivation (XCI). However, we also find subtle yet plausible evidence of escape from XCI contributing to human height. Assuming full XCI, the observed chrX contribution to complex trait heritability in both sexes is greater than expected given the presence of only a single active copy of chrX, mirroring potential dosage compensation between chrX and the autosomes. We find this enhanced contribution attributable to systematically larger active allele effects from chrX compared to autosomes in both sexes, independent of allele frequency and variant deleteriousness. Together, these findings support a model in which the two dosage-compensation mechanisms work in concert to balance the influence of chrX across the population while preserving sex-specific differences at a manageable level. Overall, our study advocates for more comprehensive locus discovery efforts in chrX.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1330-1343"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959638","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":"Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists.","authors":"Sophie Allen, Alice Garrett, Charlie F Rowlands, Miranda Durkie, George J Burghel, Rachel Robinson, Alison Callaway, Joanne Field, Bethan Frugtniet, Sheila Palmer-Smith, Jonathan Grant, Judith Pagan, Trudi McDevitt, Katie Snape, Helen Hanson, Terri McVeigh, David J Adams, Gregory M Findlay, Rehan M Villani, Amanda B Spurdle, Clare Turnbull","doi":"10.1016/j.ajhg.2025.04.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.006","url":null,"abstract":"<p><p>Advances in technology have made it possible for multiplex assays of variant effect (MAVEs) to systematically generate functional data for thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to the clinical adoption of new MAVEs. We delivered a survey during the November 2024 Cancer Variant Interpretation Group UK (CanVIG-UK) meeting comprising National Health Service (NHS) clinical scientists and clinical geneticists and received 46 responses from individuals regularly performing variant classification for diagnostic reporting. Only 35% reported they would accept clinical validation of the MAVE provided by the authors who conducted the assay; 20% reported they would attempt clinical validation themselves, and 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of a formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring central bodies on a scale of 1-5 for confidence in their review and validation of MAVEs, CanVIG-UK (median = 5), variant curation expert panels (VCEPs; median = 5), and ClinGen SVI Functional Working Group (median = 4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood of altering validation scores provided by a trusted central body). These findings, from a comparatively homogeneous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 6","pages":"1479-1488"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245921","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":"Consultation informs strategies for improving the use of functional evidence in variant classification.","authors":"Rehan M Villani, Bronwyn Terrill, Emma Tudini, Maddison E McKenzie, Corrina C Cliffe, Christopher N Hahn, Ben Lundie, Tessa Mattiske, Ebony Matotek, Abbye E McEwen, Sarah L Nickerson, James Breen, Douglas M Fowler, John Christodoulou, Lea Starita, Alan F Rubin, Amanda B Spurdle","doi":"10.1016/j.ajhg.2025.05.003","DOIUrl":"10.1016/j.ajhg.2025.05.003","url":null,"abstract":"<p><p>When investigating whether a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Functional assays of higher and higher throughput are increasingly being generated and, when appropriate, can provide strong functional evidence for or against pathogenicity in variant classification. Despite functional assay data representing unprecedented value for genomic diagnostics, challenges remain around the application of functional evidence in variant curation. To investigate a growing gap articulated in recent international studies, we surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. The survey results echo the universal difficulty in evaluating functional evidence but expand on this by indicating that even self-proclaimed expert respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified the need for support resources and educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. We then collated a list of 226 functional assays and the evidence strength recommended by 19 ClinGen Variant Curation Expert Panels. Specific assays for more than 45,000 variants were evaluated, but evidence recommendations were generally limited to lower throughput and strength. As an initial step, we provide our collated list of assay evidence as a source of international expert opinion on the evaluation of functional- evidence and conclude that these results highlight an opportunity to develop additional support resources to fully utilize functional evidence in clinical practice.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 6","pages":"1489-1495"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245918","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":"Variants in BSN, encoding the presynaptic protein Bassoon, result in a distinct neurodevelopmental disorder with a broad phenotypic range.","authors":"Stacy G Guzman, Sarah M Ruggiero, Shiva Ganesan, Colin A Ellis, Alicia G Harrison, Katie R Sullivan, Zornitza Stark, Natasha J Brown, Sajel L Kana, Anabelle Tuttle, Jair Tenorio, Pablo Lapunzina, Julián Nevado, Marie T McDonald, Courtney Jensen, Patricia G Wheeler, Lila Stange, Jennifer Morrison, Boris Keren, Solveig Heide, Meg W Keating, Kameryn M Butler, Mike A Lyons, Shailly Jain, Mehdi Yeganeh, Michelle L Thompson, Molly Schroeder, Hoanh Nguyen, Jorge Granadillo, Kari M Johnston, Chaya N Murali, Katie Bosanko, T Andrew Burrow, Syreeta Morgan, Deborah J Watson, Hakon Hakonarson, Ingo Helbig","doi":"10.1016/j.ajhg.2025.04.011","DOIUrl":"10.1016/j.ajhg.2025.04.011","url":null,"abstract":"<p><p>Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders (NDDs) and epilepsy. Here, we describe 14 individuals with de novo disruptive variants in BSN, which encodes the presynaptic protein Bassoon. To expand the phenotypic spectrum, we identified 15 additional individuals with protein-truncating variants (PTVs) from large biobanks. Clinical features were standardized using the Human Phenotype Ontology (HPO) across all 29 individuals, which revealed common clinical characteristics including epilepsy (13/29, 45%), febrile seizures (7/29, 25%), generalized tonic-clonic seizures (5/29, 17%), and focal-onset seizures (3/29, 10%). Behavioral phenotypes were present in almost half of all individuals (14/29, 48%), which included ADHD (7/29, 25%) and autistic behavior (5/29, 17%). Additional common features included developmental delay (11/29, 38%), obesity (10/29, 34%), and delayed speech (8/29, 28%). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29, 24%). To detect gene-specific signatures, we performed association analysis in a cohort of 14,895 individuals with NDDs. A total of 66 clinical features were associated with BSN, including febrile seizures (p = 1.26e-06) and behavioral disinhibition (p = 3.39e-17). Furthermore, individuals carrying BSN variants were phenotypically more similar than expected by chance (p = 0.00014), exceeding phenotypic relatedness in 179/256 NDD-related conditions. In summary, integrating information derived from community-based gene matching and large data repositories through computational phenotyping approaches, we identify BSN variants as the cause of a synaptic disorder with a broad phenotypic range across the age spectrum.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1415-1429"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109390","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 machine learning Mendelian randomization estimator applied to predict the safety and efficacy of sclerostin inhibition.","authors":"Marc-André Legault, Jason Hartford, Benoît J Arsenault, Archer Y Yang, Joelle Pineau","doi":"10.1016/j.ajhg.2025.04.010","DOIUrl":"10.1016/j.ajhg.2025.04.010","url":null,"abstract":"<p><p>Mendelian randomization (MR) enables the estimation of causal effects while controlling for unmeasured confounding factors. However, traditional MR's reliance on strong parametric assumptions can introduce bias if these are violated. We describe a machine learning MR estimator named quantile instrumental variable (Quantile IV) that achieves a low estimation error in a wide range of plausible MR scenarios. Quantile IV is distinctive in its ability to estimate nonlinear and heterogeneous causal effects and offers a flexible approach for subgroup analysis. Applying quantile IV, we investigate the impact of circulating sclerostin levels on heel bone mineral density, osteoporosis, and cardiovascular outcomes. Employing various MR estimators and colocalization techniques, our analysis reveals that a genetically predicted reduction in sclerostin levels significantly increases heel bone mineral density and reduces the risk of osteoporosis while showing no discernible effect on ischemic cardiovascular diseases. As a second application, we estimated the effect of increases in low-density lipoprotein cholesterol and waist-to-hip ratio on ischemic cardiovascular diseases using this well-known association as a positive control analysis. Quantile IV contributes to the advancement of MR methodology, and the selected applications demonstrate the applicability of our estimator in various MR contexts.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1344-1362"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085684","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":"Subcontinental genetic variation in the All of Us Research Program: Implications for biomedical research.","authors":"Mateus H Gouveia, Karlijn A C Meeks, Victor Borda, Thiago P Leal, Fernanda S G Kehdy, Reagan Mogire, Ayo P Doumatey, Eduardo Tarazona-Santos, Rick A Kittles, Ignacio F Mata, Timothy D O'Connor, Adebowale A Adeyemo, Daniel Shriner, Charles N Rotimi","doi":"10.1016/j.ajhg.2025.04.012","DOIUrl":"10.1016/j.ajhg.2025.04.012","url":null,"abstract":"<p><p>The All of Us Research Program (All of Us) seeks to accelerate biomedical research and address the underrepresentation of minorities by recruiting over 1 million participants across the United States. A key question is how self-identification with discrete, predefined race and ethnicity categories compares to genetic variation at continental and subcontinental levels. To contextualize the genetic variation in All of Us, we analyzed ∼2 million common variants from 230,016 unrelated whole genomes using classical population genetics methods alongside reference panels such as the 1000 Genomes Project, Human Genome Diversity Project, and Simons Genome Diversity Project. Our analysis reveals that participants within self-identified race and ethnicity groups exhibit gradients of genetic variation rather than discrete clusters. The distributions of continental and subcontinental ancestries show considerable variation within race and ethnicity, both nationally and across states, reflecting the historical impacts of US colonization, the transatlantic slave trade, and recent migrations. All of Us samples filled most gaps along the top five principal components of genetic variation in current global reference panels. Notably, Hispanic or Latino participants spanned much of the three-way (African, Native American, and European) admixture spectrum. Ancestry was significantly associated with body mass index (BMI) and height even after adjusting for socio-environmental covariates. In particular, West-Central and East African ancestries showed opposite associations with BMI. This study emphasizes the importance of assessing subcontinental ancestries, as the continental approach is insufficient to control for confounding in genetic association studies.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 6","pages":"1286-1301"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245920","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":"Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma.","authors":"Daniele Pepe, Xander Janssens, Kalina Timcheva, Grecia M Marrón-Liñares, Benno Verbelen, Vasileios Konstantakos, Dylan De Groote, Jolien De Bie, Amber Verhasselt, Barbara Dewaele, Arne Godderis, Charlotte Cools, Mireia Franco-Tolsau, Jonathan Royaert, Jelle Verbeeck, Kim R Kampen, Karthik Subramanian, David Cabrerizo Granados, Gerben Menschaert, Kim De Keersmaecker","doi":"10.1016/j.ajhg.2025.04.005","DOIUrl":"10.1016/j.ajhg.2025.04.005","url":null,"abstract":"<p><p>The role of synonymous mutations in cancer pathogenesis is currently underexplored. We developed a method to detect significant clusters of synonymous and missense mutations in public cancer genomics data. In melanoma, we show that 22% (11/50) of these mutation clusters are misannotated as coding mutations because the reference transcripts used for their annotation are not expressed. Instead, these mutations are actually non-coding. This, for instance, applies to the mutation clusters targeting known cancer genes kinetochore localized astrin (SPAG5) binding protein (KNSTRN) and BCL2-like 12 (BCL2L12), each affecting 4%-5% of melanoma tumors. For the latter, we show that these mutations are functional non-coding mutations that target the shared promoter region of interferon regulatory factor 3 (IRF3) and BCL2L12. This results in downregulation of IRF3, BCL2L12, and tumor protein p53 (TP53) expression in a CRISPR-Cas9 primary melanocyte model and in melanoma tumors. In individuals with melanoma, these mutations were also associated with a worse response to immunotherapy. Finally, we propose a simple automated method to more accurately annotate cancer mutations based on expressed transcripts. This work shows the importance of integrating DNA- and RNA-sequencing data to properly annotate mutations and identifies a number of previously overlooked and wrongly annotated functional non-coding mutations in melanoma.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1447-1467"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952548","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":"Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.","authors":"Thiloka Ratnaike, Ida Paramonov, Catarina Olimpio, Alexander Hoischen, Sergi Beltran, Leslie Matalonga, Rita Horváth","doi":"10.1016/j.ajhg.2025.04.003","DOIUrl":"10.1016/j.ajhg.2025.04.003","url":null,"abstract":"<p><p>The diagnosis of mitochondrial DNA (mtDNA) diseases remains challenging with next-generation sequencing, where bioinformatic analysis is usually more focused on the nuclear genome. We developed a workflow for the evaluation of mtDNA diseases and applied it in a large European rare disease cohort (Solve-RD). A semi-automated bioinformatic pipeline with MToolBox was used to filter the unsolved Solve-RD cohort for rare mtDNA variants after validating this pipeline on exome datasets of 42 individuals previously diagnosed with mtDNA variants. Variants were filtered based on blood heteroplasmy levels (≥1%) and reported association with disease. Overall, 10,157 exome and genome datasets from 9,923 affected individuals from 9,483 families within Solve-RD met the quality inclusion criteria. 136 mtDNA variants in 135 undiagnosed individuals were prioritized using the filtering approach. A focused MitoPhen-based phenotype similarity scoring method was tested in a separate genetically diagnosed \"phenotype test cohort\" consisting of nuclear gene and mtDNA diseases using a receiving operator characteristic evaluation. We applied the MitoPhen-based phenotype similarity score of >0.3, which was highly sensitive for detecting mtDNA diseases in the phenotype test cohort, to the filtered cohort of 135 undiagnosed individuals. This aided the prioritization of 34 out of 37 (92%) individuals who received confirmed and likely causative mtDNA disease diagnoses. The phenotypic evaluation was limited by the quality of input data in some individuals. The overall pipeline led to an additional diagnostic yield of 0.4% in a cohort where mitochondrial disease was not initially suspected. This highlights the value of our mtDNA analysis pipeline in diverse datasets.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1376-1387"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962690","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":"Benefits and barriers to broad implementation of genomic sequencing in the NICU.","authors":"Melissa R Goldin, Douglas M Ruderfer, Alexander Bick, Dan M Roden, Bryce A Schuler, Jamie R Robinson","doi":"10.1016/j.ajhg.2025.04.007","DOIUrl":"10.1016/j.ajhg.2025.04.007","url":null,"abstract":"<p><p>Genome (GS) and exome (ES) sequencing as first-tier diagnostic tests have the potential to increase rates of genetic diagnoses and acutely change the management of neonates in the neonatal intensive care unit (NICU). However, the widespread implementation of genomic sequencing has been limited by several barriers. In this systematic review, we analyze the current literature on the utilization of GS and ES in infants in the NICU to identify the benefits, barriers, and components of successful implementation. Across the 42 studies that discussed GS and ES in the NICU setting, six themes were identified: disease detection, timeliness of results, cost, provider attitudes, parental attitudes, and equitable access. Benefits of GS and ES include high disease detection rates, timely results, and possible reduction in healthcare costs by reducing time spent in the NICU. Additionally, clinicians find GS/ES to be important and useful, and parents and caregivers largely perceive GS/ES to be beneficial. Barriers to widespread GS/ES include availability of personnel to facilitate timely diagnosis and coverage of cost. Additionally, clinicians report worries about a lack of genetics knowledge, informed consent, results return, and potential harm. Parents consistently report low levels of anxiety, decisional conflict, harm, or regret. Finally, the lack of availability of translated consent documents limits the participation of families who do not speak English or Spanish. Continued work is essential to optimize these technologies and ensure equitable access.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1270-1285"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075502","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":"Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation.","authors":"Min Seon Park, Runjun D Kumar, Cristian Ovadiuc, Andrew Folta, Abbye E McEwen, Ashley Snyder, Rehan M Villani, Amanda B Spurdle, Douglas M Fowler, Alan F Rubin, Brian H Shirts, Lea M Starita, Andrew B Stergachis","doi":"10.1016/j.ajhg.2025.04.009","DOIUrl":"10.1016/j.ajhg.2025.04.009","url":null,"abstract":"<p><p>Variant-level functional data are a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUSs). However, the usage of functional data by genetics professionals is currently unknown. An online survey was developed and distributed in the spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting, and overall, respondents felt confident assessing functional data. However, 67% indicated that functional data for variants of interest were rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to their use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support the use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 6","pages":"1468-1478"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245919","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}