American journal of human genetics最新文献

{"title":"Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.","authors":"Susan M Hiatt, Wenjing Zhao, Zhongqing Wang, Yingjie Wan, Kewen Chen, Ke Wang, Senwei Tan, Magalie Barth, Gaber Bergant, Thomas Besnard, Emily Boothe, Theresa Brunet, Caleb Bupp, Benjamin Cogne, Julie S Cohen, Christine Coubes, Bert B A de Vries, Madison Donald, Colin A Ellis, Stephanie Riley Eriksson, Benjamin Ganne, David Genevieve, Benedicte Gerard, Aixa Gonzalez Garcia, Laura G Hendon, Noa Henig, Kristina Huss, Bertrand Isidor, Taylor Laut, Benjamin R Leadem, Elysa J Marco, Daphna Marom, Saadet Mercimek-Andrews, Alison M Muir, Benjamin Navet, Slavica Ostojić, Borut Peterlin, Rolph Pfundt, Anna Prentice, Clement Prouteau, Bethany Robinette, Dmitrijs Rots, Gita Taurina, Marjon van Slegtenhorst, Ludmila Volozonoka, Marja Wessels, Brayden West, Ayelet Zerem, Yinhong Zhang, Baosheng Zhu, Alban Ziegler, Cécile Courdier, Patricia Fergelot, Julien Van Gils, Shannon Terek, Grace E VanNoy, Brianna Berlin, Alexandra G Buonomo, Jillian L McKee, Gregory M Cooper, Hui Guo","doi":"10.1016/j.ajhg.2026.08.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.013","url":null,"abstract":"<p><p>ZNF536 encodes a C2H2 zinc-finger transcription factor that functions as a transcriptional repressor. While common noncoding variants at the ZNF536 locus have been reported to be associated with schizophrenia in a genome-wide association study (GWAS), the contribution of rare, protein-altering variants to human disease has not been systematically investigated. Through an international collaboration, we assembled a cohort of 21 affected individuals carrying 18 unique, rare, heterozygous, protein-altering ZNF536 variants. Most variants (15/18) were predicted loss-of-function (LoF) alleles, with the remainder being missense variants. Among families with available inheritance data (17/20), most variants arose de novo (12/17), while others were inherited from mosaic or mildly affected parents (5/17). Clinically, affected individuals presented with developmental delay along with high rates of autism spectrum disorder, intellectual disability, hyperactivity, aggressive behavior, anxiety, and hyperphagia; epilepsy and sleep disturbances were also frequently observed. To assess functional consequences of a proband-associated ZNF536 variant, we generated a Zfp536^p.Gln169Ter knock-in mouse model. Homozygous mutants were non-viable, while heterozygotes survived but displayed autism-like behaviors, increased anxiety, and impaired recognition memory. Embryonic brain analysis revealed reduced cortical size, cortical thickness, and decreased deep-layer neuronal density. These features are consistent with phenotypes of a publicly available mouse knockout model and support our clinical cohort findings that rare monoallelic LoF variants in ZNF536 underlie a genetic neurodevelopmental disorder characterized by developmental delay, autism, and behavioral dysregulation. The pathogenicity of missense variants in disease remains to be determined. These results support a role for ZNF536 as a dosage-sensitive regulator of cortical development.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890739","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":"Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders.","authors":"Julian Fuhrer, Alexey A Shadrin, Timothy Hughes, Nadine Parker, Guy Hindley, Evgeniia Frei, Dat Nguyen, Olav B Smeland, Srdjan Djurovic, Ole A Andreassen, Anders M Dale, Oleksandr Frei","doi":"10.1016/j.ajhg.2026.08.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.012","url":null,"abstract":"<p><p>The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across 74 functional annotations covering exonic, intronic, and intergenic regions for 34 complex traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons account for a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less-polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of the broader set of functional annotations also reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less-polygenic traits show stronger contributions from promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, shifting from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890729","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":"RNA splicing evidence enables robust classification of BRCA1 exon 18 variants: Results from the ENIGMA consortium.","authors":"Joanna Domènech-Vivó, Hélène Tubeuf, Romy L S Mesman, Aurelie Drouet, Mélanie Girardi, María Concepción Alonso-Cerezo, Diana Baralle, Nadia Boutry-Kryza, David J Bunyan, Helen J Byers, Sandrine M Caputo, Kathleen B M Claes, Miguel De la Hoya, D Gareth Evans, Laure Frésard, Sophie Krieger, Conxi Lázaro, Mélanie Leone, Eva Macháčková, Mireia Menéndez, Alejandro Moles-Fernández, Gemma Montalban, Erin Mundt, Marcy E Richardson, Elke M Van Veen, Jamie Weyandt, Judith Balmaña, Amanda B Spurdle, Orland Diez, Maaike P G Vreeswijk, Alexandra Martins, Sara Gutiérrez-Enríquez","doi":"10.1016/j.ajhg.2026.08.001","DOIUrl":"10.1016/j.ajhg.2026.08.001","url":null,"abstract":"<p><p>The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) research consortium conducted a comprehensive study to characterize spliceogenic variants in BRCA1 exon 18. The absence of systematic RNA-based assessment for these variants has led to inconsistent interpretation, limiting accurate classification and management of individuals and their families. The splicing profile of 166 variants was assessed using minigene assays; 32 were additionally analyzed in blood-derived RNA from 51 individuals and 18 in mouse embryonic stem cell (mESC)-based assays to evaluate homology-directed repair (HDR) capacity. mRNA assessment by RT-PCR in blood samples and minigene assays showed a significant positive correlation, with splicing analysis in mESCs displaying highly concordant results. The mESC-based HDR assay showed that the in-frame exon 18 skipping (Δ18) transcript encodes a non-functional protein lacking rescue activity. Linear regression analysis using mESC splicing and functional data indicated that ≥59% of full-length (FL) levels and <34% of Δ18 were associated with benign HDR activity. These thresholds differ from those recommended by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) specifications for applying BP7_strong(RNA): >30% functional transcripts or <70% non-functional transcripts. Incorporation of RNA splicing evidence into variant interpretation increased pathogenic (28.6%-31.7%) and benign (3.7%-24.4%) classifications while reducing likely pathogenic (19.5%-17.7%), uncertain (18.9%-8.5%), and likely benign (29.3%-17.7%) categories. Experimental mRNA profiling impacted the interpretation of 34% of variants and resolved uncertainty in approximately 10% of cases. Exon 18 skipping was less tolerated, indicating that the degree of splice perturbation required to impair BRCA1 function may depend on the nature of the resulting non-functional transcript.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1894-1915"},"PeriodicalIF":7.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817213","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":"Distinct mutational landscapes for germline and somatic cancer variants in forty tumor suppressor genes.","authors":"Suhasini D Lulla, Deborah I Ritter, Chimene Kesserwan, Sharon E Plon","doi":"10.1016/j.ajhg.2026.08.003","DOIUrl":"10.1016/j.ajhg.2026.08.003","url":null,"abstract":"<p><p>Germline and somatic cancer variants in tumor suppressor genes (TSGs) share loss-of-function mechanisms, but studies of a few genes (DICER1 and CEBPA) have demonstrated differences in variant consequence and location. To systematically assess whether TSGs display distinct mutational patterns, we leveraged large public genetic databases and compared 32,941 high-quality pathogenic/likely pathogenic (P/LP) germline variants in ClinVar, with 12,907 oncogenic/likely oncogenic (O/LO) somatic tumor variants from cBioPortal across 40 TSGs. Only 3,863 (9.2%) variants were shared. Eighteen TSGs showed significantly different distributions of variant occurrences by molecular consequence, replicated with non-overlapping somatic data from the COSMIC database (chi-squared tests, false discovery rate = 5%). DICER1, TP53, and SMAD4 displayed excess somatic missense events, while nine TSGs (e.g., RB1 and APC) contained excess somatic stop-gain events throughout the coding sequence. Analysis by tumor type revealed excess stop-gain events in tissues exposed to environmental mutagens with corresponding mutation signatures. For several TSGs (WT1), germline variants predispose to tumors (Wilms' tumor) distinct from the majority source of somatic data (myeloid leukemia). Germline and somatic events are also distributed unevenly across cDNA locations, with 103 regions of preferential clustering in 39 TSGs (78 somatic and 25 germline). Twenty somatic clusters contained recurring frameshifts in homopolymer runs, many in tumors with microsatellite instability. Germline clusters contain more germline-exclusive variants, some driving non-cancer phenotypes reflecting genetic pleiotropy. Altogether, germline and somatic variants of TSGs represent unique sets with substantially different patterns shaped by selection pressures from gene-specific and somatic mutational mechanisms. Characterizing these distinctions enables more accurate clinical interpretation of TSG variants.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1929-1945"},"PeriodicalIF":7.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenome- and laboratory-wide meta-analyses of sickle cell trait reveal multi-system disease associations","authors":"Micah R. Hysong,Megan M. Shuey,Tyne W. Miller-Fleming,Karl Keat,Adrienne M. Stilp,Yun Li,Nancy J. Cox,Paul L. Auer,Nora Franceschini,Anurag Verma,Laura M. Raffield,Alexander P. Reiner","doi":"10.1016/j.ajhg.2026.08.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.010","url":null,"abstract":"Sickle cell trait (SCT) is increasingly recognized as a risk factor for adverse health outcomes. We utilized three large US electronic health record-based biobanks (Vanderbilt University Medical Center’s BioVU, Penn Medicine Biobank, and All of Us) to conduct phenome-wide association (PheWAS) and clinical laboratory-wide association (LabWAS) meta-analyses of 4,813 individuals with SCT among 58,830 African genetic ancestry participants (∼60% female). Significant associations were replicated using a published PheWAS of SCT from the Million Veteran Program. Our PheWAS meta-analysis confirmed the association of SCT with increased risks of kidney disease, pulmonary embolism, and anemia, while also identifying associations with increased risk of splenomegaly, gout, acute pyelonephritis, and anemia of pregnancy. LabWAS confirmed prior associations of SCT with blood cell counts, red cell indices, kidney function, and urinary concentrating ability. We also identified associations with higher serum electrolytes, bilirubin, and reticulocyte count and lower blood urea nitrogen and platelet count. In sex-stratified analyses, the association of SCT with kidney-related disorders and kidney dysfunction was stronger in females, while the association with platelet and lymphocyte phenotypes was greater in males with SCT. Our results provide insights into the multi-system complications of SCT and have potential clinical implications both for general awareness of susceptibility and appropriate reference ranges for various clinical laboratory parameters in individuals with SCT.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"55 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877382","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":"Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome","authors":"Kimberley Jade Anderson,Eirny Tholl Thorolfsdottir,Ilana M. Nodelman,Sara Tholl Halldorsdottir,Stefania Benonisdottir,Malak A. Alghamdi,Naif A.M. Almontashiri,Brenda J. Barry,Matthias Begemann,Jacquelyn F. Britton,Sarah Burke,Benjamin Cogne,Ana S.A. Cohen,Carles de Diego Boguñá,Evan E. Eichler,Elizabeth C. Engle,Jill A. Fahrner,Laurence Faivre,Mélanie Fradin,Nico Fuhrmann,Christine W. Gao,Gunjan Garg,Dagmar Grečmalová,Mina Grippa,Jacqueline R. Harris,Kendra Hoekzema,Tova Hershkovitz,Sydney Hubbard,Katrien Janssens,Julie A. Jurgens,Stanislav Kmoch,Cordula Knopp,Meral Aktas Koptagel,Farah A. Ladha,Pablo Lapunzina,Tobias Lindau,Marije Meuwissen,Andreina Minicucci,Emily Neuhaus,Mathilde Nizon,Lenka Nosková,Kristen Park,Chirag Patel,Rolph Pfundt,Pankaj Prasun,Nils Rahner,Nathaniel H. Robin,Carey Ronspies,Jasmin Roohi,Jill Rosenfeld,Margarita Saenz,Carol Saunders,Zornitza Stark,Isabelle Thiffault,Sarah Thull,Danita Velasco,Clara Velmans,Jolijn Verseput,Antonio Vitobello,Tianyun Wang,Karin Weiss,Ingrid M. Wentzensen,Genay Pilarowski,Thor Eysteinsson,Madelyn Gillentine,Kári Stefánsson,Agnar Helgason,Gregory D. Bowman,Hans Tomas Bjornsson","doi":"10.1016/j.ajhg.2026.08.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.005","url":null,"abstract":"Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"35 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877384","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":"Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.","authors":"Yong-Han Hank Cheng, Adriana E Sedeño-Cortés, Jane E Ranchalis, Katherine M Munson, Mitchell R Vollger, Elsa Balton, Casie A Genetti, Jenny L Wilson, Monica H Wojcik, Alan H Beggs, Michael J Bamshad, Chia-Lin Wei, Katrina M Dipple, Runjun D Kumar, Mark D Fleming, Ian A Glass, Elizabeth E Blue, Gail Jarvik, Jessica X Chong, Daniela M Witten, Anne O'Donnell-Luria, Andrew B Stergachis","doi":"10.1016/j.ajhg.2026.08.002","DOIUrl":"10.1016/j.ajhg.2026.08.002","url":null,"abstract":"<p><p>Identifying pathogenic non-coding variants that contribute to Mendelian conditions remains challenging, as the functional impact of these variants on gene function is often unknown. We present IsoRanker, a long-read transcriptome sequencing-based framework that prioritizes functionally relevant variants by detecting genes and isoforms with outlier expression, allelic imbalance, and/or nonsense-mediated decay (NMD). We generated paired cycloheximide-treated and untreated fibroblast transcriptomes from 31 individuals (3 individuals with known transcript-altering rare variants and 28 individuals with unsolved conditions) and linked transcripts to phased long-read genomes. IsoRanker successfully recovered known transcript alterations in this cohort, and exploratory subsampling analyses suggested that their prioritization was largely preserved down to cohorts of 11 individuals and ∼5 million full-length transcripts per individual. Performance was dependent upon de novo isoform caller choice, particularly for NMD-sensitive and previously unannotated isoforms. Among 28 previously unsolved cases, IsoRanker deprioritized 8 out of 10 fibroblast-expressed candidate splice-site variants while nominating 4 new leads. In one individual, IsoRanker prioritized HARS1, revealing bi-allelic non-coding variants that together produced a partial HARS1 loss of function and informed targeted therapy in this individual. These findings support long-read, NMD-aware transcriptomics with IsoRanker as an effective approach for generating isoform-level functional evidence, improving classification of non-coding variants and supporting the diagnosis of individuals with rare genetic conditions.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1812-1831"},"PeriodicalIF":7.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817263","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":"Mutation rate heterogeneity biases variant effect prediction and reveals genuine mutational robustness","authors":"Hossameldin Loay,Prathitha Kar,Evan Koch,Vladimir Seplyarskiy,Donate Weghorn","doi":"10.1016/j.ajhg.2026.08.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.011","url":null,"abstract":"Variant effect predictors (VEPs) are widely used to interpret the functional consequences of human genetic variation. Because most methods rely on sequence conservation, they implicitly treat conservation as evidence of functional constraint. However, substitution patterns across a phylogeny reflect not only selection but also differences in underlying mutation rates. Here, we show that this creates a systematic confounding: most VEPs capture mutation rate variation and misinterpret it as variation in functional importance. Widely used conservation metrics exhibit a related bias; in particular, phyloP scores correlate strongly with mutation rate even at putatively neutral sites. Consequently, variants at low-mutation-rate sites tend to be predicted as more damaging, and variants at highly mutable sites as more tolerated, than warranted by their true functional impact. We also identify a distinct biological signal in experimental measurements of mutational effects on protein stability: amino acid substitutions that are more likely to arise are, on average, less destabilizing than rarer substitutions. This provides empirical support for mutational robustness in the context of protein stability. However, this relationship is insufficient to explain the mutation-rate dependence observed in current VEP outputs. Together, our findings show that mutation rate heterogeneity systematically biases current variant effect prediction frameworks, highlight the need to model mutation probabilities explicitly in future VEPs, and reveal a genuine biological signal of mutational robustness.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877380","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":"Systematic and proactive evaluation of AIRE missense variant effects.","authors":"Anna Axakova, Amund H Berger, Warren van Loggerenberg, Nishka Kishore, Marinella Gebbia, Megan X Ding, Samuel V Douville, Daniel R Tabet, Atina G Cote, Jochen Weile, Stefan Johansson, Eirik Bratland, Frederick P Roth","doi":"10.1016/j.ajhg.2026.07.008","DOIUrl":"10.1016/j.ajhg.2026.07.008","url":null,"abstract":"<p><p>Pathogenic variants in the autoimmune regulator (AIRE) cause autoimmune polyendocrine syndrome type 1 (APS-1), a rare primary immunodeficiency disease with symptoms including hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis. AIRE increases the expression and presentation of tissue-specific genes expressing \"self\" antigens in the developing T cell niche, thus triggering the elimination of self-reactive T cells and preventing autoimmunity. Earlier diagnoses can benefit those with APS-1, and APS-1 diagnosis by AIRE sequencing is increasingly common. However, two-thirds of reported clinical variants are missense, and more than half of these are variants of uncertain significance (VUSs). Cell-based variant functional assays can provide strong evidence toward more informative variant classification, but these are carried out reactively, often years after clinical presentation. By contrast, proactively assessing all possible missense variants could provide immediate evidence to guide genetic diagnosis, even for never-before-seen variants. Here, we used an insulin-promoter-driven reporter to proactively assess the function of 9,790 AIRE missense variants. The resulting AIRE variant effect map both validates and extends current biochemical knowledge, concords with pathogenicity annotations, and provides proactive evidence for 70% of previously reported VUSs. Placing our map in the context of both an international APS-1 cohort and the UK Biobank revealed quantitative genotype-phenotype correlations. Moreover, evidence from our variant effect map resolved 32% of current VUSs. Together, our proactive resource of AIRE variant impacts offers the potential to improve outcomes via more rapid and definitive APS-1 diagnosis.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1873-1893"},"PeriodicalIF":7.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683211","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 phenotypic paradigm for cerebral palsy genetics","authors":"Adam S. Arterbery,Michael A. Gargano,Anita Bagley,Jagadish Chandrabose Sundaramurthi,Lauren Rekerle,Thania Ordaz-Robles,Daniel Danis,Adam S.L. Graefe,Ana L. Arenas-Díaz,Jeremy P. Bauer,Hannah Blau,Leigh Carmody,Kristen I. Carroll,Janice Davis,Philip F. Giampietro,Anxhela Gjyshi Gustafson,Monserat Hernandez,Julius O.B. Jacobsen,Paige Lemhouse,David Millet,Shubhra Mukherjee,Patrick S. Nairne,Emily Nice,Talia Plotkin,Kenneth Powell,Lukas Ramlow,Ellen M. Raney,Mallory Shingle,Damian Smedley,Peter A. Smith,Demiana A. Soliman,David E. Westberry,Jon R. Davids,Peter N. Robinson","doi":"10.1016/j.ajhg.2026.08.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.007","url":null,"abstract":"Cerebral palsy (CP) represents a clinically and etiologically heterogeneous group of permanent but not unchanging disorders of movement, posture, and motor function resulting from non-progressive disturbances of the developing fetal or infant brain. Pathogenic variants in Mendelian disease-associated genes can be found in a subset of individuals with CP, with variants deemed causal of CP having been published for at least 515 genes. Currently, controversy exists as to whether to interpret such pathogenic variants as causing CP, whether the diagnosis instead should be “CP mimic,” or whether a clinical diagnosis of CP should coexist with the molecular diagnosis of a Mendelian disease. Accordingly, there is no universally accepted model of the genetic architecture of CP. Here, we present a statistical approach that treats CP as a phenotypic feature for which some genetic disorders confer an increased risk. Based on comprehensive literature curation, we show that the null hypothesis of no CP association can be rejected for only 89 of the 515 genes. We applied these findings to the analysis of a cohort of 460 children diagnosed with CP in the Shriner Children’s network who underwent genome sequencing. We identified pathogenic or likely pathogenic (P/LP) variants in 60 genes in 15.8% of the children. Only 16 of the 60 genes had significant evidence for CP association in our literature analysis. Our results suggest that a stratified approach to attributing causality to genetic variants in CP could support precision genomic medicine for affected individuals.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"17 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877381","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}