American journal of human genetics最新文献

{"title":"De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes","authors":"Jasmin Lisfeld,Ivan K. Chinn,Bo Yuan,Christian Casar,Christian Müller,Eyal Elron,Gal Zaks Hoffer,Naama Orenstein,Kristian Tveten,Julian Delanne,Hana Safraou,Anne-Sophie Denommé-Pichon,Erfan Aref-Eshghi,Nathaniel H. Robin,Elizabeth D. Rothrock,Ingrid M. Wentzensen,Gwendolyn J. Messer,Rhonda E. Schnur,Rachel Rabin,Sivan Lewis,Frank Sleutels,Sarina G. Kant,James R. Lupski,Kerstin Kutsche,Frederike L. Harms","doi":"10.1016/j.ajhg.2026.09.018","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.018","url":null,"abstract":"SRSF3 (SRp20), a member of the serine/arginine-rich protein family of splicing factors, plays a central role in constitutive and alternative splicing. The C-terminal arginine/serine-rich domain of SRSF3 undergoes dynamic phosphorylation cycles that regulate its subcellular localization, protein-protein interactions, and nuclear mRNA export while also indirectly modulating the RNA-binding capability. We report nine individuals with variable developmental phenotypes, including developmental delay and/or mild to moderate intellectual disability as the most consistent feature, and de novo SRSF3 variants. These variants comprise c.181G>C (p.Asp61His) and c.242C>G (p.Ser81Trp), affecting highly conserved residues within the RNA recognition motif, c.330_331del (p.Pro111Serfs∗20), c.402_403del (p.Arg137Ilefs∗16), c.477dup (p.Ser160Valfs∗3), and a recurrent nonsense variant c.445C>T (p.Arg149∗). For c.330_331del, nonsense-mediated mRNA decay (NMD) was predicted. Qualitative RT-PCR followed by Sanger sequencing and RNA sequencing (RNA-seq) of fibroblasts from this individual demonstrated NMD of SRSF3 transcripts containing the variant. However, overall SRSF3 mRNA and protein levels were comparable to control cells, suggestive of a compensatory mechanism acting in these cells. Comprehensive functional studies of ectopically expressed SRSF3Asp61His, SRSF3Ser81Trp, SRSF3Arg137Ilefs∗16, SRSF3Arg149∗, and SRSF3Ser160Valfs∗3 in HEK293T cells revealed reduced complex formation with polyadenylated RNA as well as intrinsic instability of C-terminally truncated variant proteins, correlating with decreased C-terminal phosphorylation. Complex formation with the nuclear export proteins YTHDC1 and NXF1 was reduced for SRSF3Arg137Ilefs∗16 and SRSF3Arg149∗ and increased for SRSF3Ser81Trp. Additionally, nucleocytoplasmic shuttling, assessed in HeLa cells, was reduced for the C-terminally truncated SRSF3 variant proteins. Together, our data demonstrate distinct functional defects for the disease-associated SRSF3 variants, which may underlie phenotypic variability in affected individuals.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"9 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221609","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":"The genetic architecture of pentanucleotide repeat variation and disease association.","authors":"Isaac R L Xu, David Pellerin, Liedewei Van De Vondel, Ben Weisburd, Egor Dolzhenko, Matt C Danzi, Stephan Zuchner","doi":"10.1016/j.ajhg.2026.09.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.017","url":null,"abstract":"<p><p>Pentanucleotide tandem repeats (PNTRs) are associated with at least eleven neurological disorders in which pathogenic alleles are defined by both large repeat expansions and disease-specific non-reference motifs. However, population-scale, sequence-resolved datasets of PNTR variation have not been available, limiting interpretation of repeat alleles identified through long-read sequencing. Here, we genotyped 47,952 PNTR loci in 543 high-coverage PacBio HiFi genomes spanning five ancestry superpopulations, with validation in 500 Oxford Nanopore genomes. Using base-pair-resolved decomposition, we generated a genome-wide reference of PNTR length and sequence variation. Disease-associated PNTR loci emerged as extreme outliers for repeat-length variability, extreme allele length, and motif diversity. Sequence-resolved analyses further revealed that repeat length and sequence composition are frequently coupled, whereby alleles of distinct motif and interruption configurations occupy discrete length ranges. Finally, haplotype-resolved analyses showed that repeat variability and disease association converge on specific chromosomal backgrounds, exemplified by the SAMD12 locus. Together, these findings establish principles of PNTR variation for interpreting repeat alleles, prioritizing candidate loci, and discovering novel repeat expansion disorders.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206311","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":"Accurate detection of sub-1% frequency somatic mutations by whole-genome sequencing","authors":"Yeongjun Jang,Stephanie Gardiner,Yifan Wang,Abhiram Natu,Mrunal K. Dehankar,Livia Tomasini,Arijit Panda,Carrie Cibulskis,Lisa Anderson,Tim H.H. Coorens,Ji Won Oh,Alexander E. Urban,Kristin Ardlie,Gabor Marth,Flora M. Vaccarino,Alexej Abyzov","doi":"10.1016/j.ajhg.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.010","url":null,"abstract":"Continuous advances in read accuracy have positioned bulk whole-genome sequencing as a promising approach for somatic mutation discovery in research and clinical settings, but its utility for detecting low-frequency mutations in high-coverage data has not been thoroughly assessed. We utilized an experimental design featuring (1) primary human fibroblasts with naturally occurring mutations and expanded subclonal populations, (2) induced pluripotent stem cell (iPSC) lines corresponding to subclones, and (3) additional iPSC lines originating from other fibroblasts from the same donor, enabling comprehensive evaluation of mutation detection across analytical methods and sequencing depths. Mutations discovered in iPSC lines defined positive control mutations ranging from 0.1% to 25% variant allele fraction (VAF) and negative (i.e., absent) control mutations in fibroblasts. Using the negative controls, we determined PacBio and AVITI as the most accurate sequencing platforms in “easy” (i.e., reliably accessible by short reads) and “non-easy” genomic regions, respectively. AVITI was also the most accurate for indel sequencing. We benchmarked mutation detection in fibroblasts in “easy” regions using ∼1,360× Illumina short-read data for mutation discovery and combined ∼600× PacBio and AVITI data for confirmation. Our analyses demonstrated accurate and specific detection of point mutations below 1% VAF and non-homopolymer indels down to 1% VAF. Homopolymer indels could be reliably detected only at VAF >3%. Mutation detection was degraded in postmortem samples, for which we provide recommendations for additional filtering and data-quality assessment. Finally, we show that combining ∼200× coverage across tissues from a donor is a feasible strategy for detecting developmental mutations shared across tissues.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173054","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":"De novo MAP2K4 variants cause a neurodevelopmental syndrome and impaired JNK signaling in iPSC-derived neurons","authors":"Tomoki T. Nomakuchi,Alyssa L. Rippert,Sabrina A. Santos De León,Elizabeth M. Gonzalez,Dong Li,Rajesh Angireddy,Livia Sertori Finoti,Flavio Faletra,Luciana Musante,Rinne Tuula,David J. Amor,Lydia von Wintzingerode,Rami Abou Jamra,Samantha R. Stover,Jillian G. Buchan,Jennifer Hayek,Eyby Leon,Tania Attie-Bitach,Marlene Rio,Genevieve Baujat,Elisabeth Wallach,Amandine Smail,Kerith-Rae Dias,Ulrich Pfeifer,Amanda Peterson,Rebecca C. Ahrens-Nicklas,Elizabeth J.K. Bhoj","doi":"10.1016/j.ajhg.2026.09.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.014","url":null,"abstract":"MAP2K4 encodes a kinase that activates the c-Jun N-terminal kinase (JNK) pathway, which is essential for human neurodevelopment. While somatic MAP2K4 loss has been observed in cancer, germline variants have not previously been linked to human disease. We describe nine individuals with de novo MAP2K4 variants and one individual with a MAP2K4 variant of unknown inheritance who present with a syndromic neurodevelopmental disorder. Shared features include developmental delay or intellectual disability, epilepsy, and variable congenital malformations, most commonly affecting the genitourinary system. To define the mechanism, we generated CRISPR-edited induced pluripotent stem cell (iPSC)-derived neurons with MAP2K4 deficiency. These neurons showed reduced JNK pathway activation and impaired maturation in the neurogenin 2 (NGN2) system, characterized by persistence of progenitor-like cells and disrupted neurite morphology. Our findings establish MAP2K4 as a Mendelian neurodevelopmental disorder-associated gene and identify impaired JNK signaling as the underlying mechanism. More broadly, this work expands the spectrum of JNK pathway disorders and underscores the critical role of JNK signaling in human brain development.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"31 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152662","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":"Large-scale integration of functional assay data for the resolution of germline BRCA1 and BRCA2 variants of uncertain significance","authors":"Paulo C.M. Lyra Jr.,Samuel Brito,Michael Parsons,Chunling Hu,Thales C. Nepomuceno,Nam Phuong Nguyen,Lucas Dalcolmo,Marcy E. Richardson,Geise de Oliveira,João da Silva,Laura Caleca,Huaizhi Huang,Sounak Sahu,Muthiah Bose,Maria Rossing,Phoebe Dace,Gregory M. Findlay,Rehan Villani,Aditi Hazra,Alexandra Martins,Sandrine M. Caputo,Gael A. Millot,Joanne Ngeow Yuen Yie,Marcelo A. Carvalho,Melissa S. Cline,Paolo Radice,Romy L.S. Mesman,Valentina Zampiga,Vijai Joseph,Katherine L. Nathanson,Kyriaki Michailidou,Edwin S. Iversen Jr.,Shyam Sharan,Amanda B. Spurdle,Maaike P.G. Vreeswijk,Fergus J. Couch,Alvaro N.A. Monteiro,the ENIGMA Consortium","doi":"10.1016/j.ajhg.2026.09.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.013","url":null,"abstract":"Carriers of BRCA1 and BRCA2 pathogenic variants are at a significantly elevated risk for several cancers. Widespread germline genetic testing has led to a significant increase in the detection of variants of uncertain significance (VUSs) in these genes. To assess variant pathogenicity, we curated, harmonized, and integrated functional data for 3,247 BRCA1 and 6,177 BRCA2 missense variants derived from BRCA1/2 functional assays. Functional results were harmonized across studies by converting data into ordinal categorical variables. We applied ClinGen variant interpretation guidelines for each assay to assign evidence for or against pathogenicity. Final evidence criteria for each variant were obtained through the integration of results from different assays, and large case-control studies confirmed that benign and pathogenic variants categorized using the integrated functional framework are associated with low and high risk for breast cancer, respectively. Next, we integrated additional sources of data, leading to resolution of 80.1% of BRCA1 VUSs and 69.5% of BRCA2 VUSs and classification of 6,517 (2,345 in BRCA1 and 4,172 in BRCA2) missense variants.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"16 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151817","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":"Loss of the human BRIP1 C terminus does not cause Fanconi anemia","authors":"Anja Droste,Alexandra Sobeck,Jost Knaup,Isabell Popp,Julia Vodopiutz,Andreas-Robert Janecke,Britta Fiebig,Monika Maringa,Ulrike Faust,Natalie Carter,Robert Maiwald,Leo Kager,Jan Hauke,Detlev Schindler,Regina Hark,Viola Lalomia,Renata Kulka,Christian P. Kratz,Anna Repczynska,Reinhard Kalb","doi":"10.1016/j.ajhg.2026.09.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.009","url":null,"abstract":"Fanconi anemia (FA) is a genetic disorder characterized by congenital anomalies, progressive bone marrow failure, and an increased cancer risk. FA patient cells are hypersensitive to DNA interstrand crosslinks (ICLs), which cause chromosomal and genomic instability if left unrepaired. We identified 11 individuals from seven families who are homozygous for one of two C-terminally truncating variants in BRIP1 (previously known as FANCJ), c.2947del (p.Ile983Leufs∗2) (n = 3) or c.2992_2995del (p.Lys998Glufs∗60) (n = 8). None of them exhibited hematologic manifestations of FA, including bone marrow failure, myelodysplasia, or any FA-associated early-onset cancer types. Patient-derived blood cells showed stable levels of the BRIP1 p.Ile983Leufs∗2 variant and were resistant to ICL-inducing agents. In contrast, cells containing the BRIP1 p.Lys998Glufs∗60 variant displayed partial BRIP1 degradation and a mild cellular phenotype, evidenced by intermediate ICL sensitivity and a moderately elevated rate of ICL-induced chromosomal breaks. An isogenic BRIP1 knockout cell model expressing either wild-type or variant BRIP1 fully recapitulated these phenotypes. Introducing a stop codon at position 998 (p.Lys998∗) resulted in wild-type-like protein stability and ICL resistance, demonstrating that the aberrant frameshift extension, rather than C-terminal truncation, causes the observed cellular ICL sensitivity. Further deletion analyses revealed that the BRIP1 helicase domain (amino acids 1–888) is required and sufficient for cellular ICL resistance. BRCA1 interaction with phosphorylated BRIP1 Ser990 is dispensable for ICL repair. Our findings indicate that FA can result from the loss of the N-terminal helicase domain of BRIP1 but not from the loss of its C-terminal functions.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151857","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 massively parallel reporter assay of MECP2cis-regulatory elements reveals genetic candidates for male-biased autism.","authors":"Rebecca Meyer-Schuman, Fisher Cherry, Yang Sui, Athanasios Papastathopoulos-Katsaros, Yi Zhong, Yidan Li, Tianyun Wang, Kelsey Hennick, Druha Karunakaran, Hanna Berk-Rauch, Zhandong Liu, Aravinda Chakravarti, Tomasz Nowakowski, Evan E Eichler, Huda Zoghbi","doi":"10.1016/j.ajhg.2026.09.011","DOIUrl":"10.1016/j.ajhg.2026.09.011","url":null,"abstract":"<p><p>Autism affects male individuals four times more often than female individuals, yet the basis of this sex bias remains unclear. One hypothesis is that this sex bias is due to genetic variants in X chromosome genes where haploinsufficiency causes neurodevelopmental disorders (NDDs). In heterozygous XX female probands, a complete loss-of-function variant in one of these genes often causes syndromic NDD, but the same variant is too deleterious for survival in hemizygous XY males. A mild hypomorphic variant, however, may be tolerated in a female carrier but may produce milder neurological phenotypes in a male proband. We tested this by investigating cis-regulatory elements (CREs) of MECP2, a dosage-sensitive gene on the X chromosome where total loss-of-function variants cause Rett syndrome in female children and severe, usually fatal neonatal encephalopathies in male infants. Using a massively parallel reporter assay in human neurons, we mapped transcription factor binding sites within MECP2 CREs and tested autism-associated variants for functional impact. We identified two noncoding variants that change CRE activity and are associated with male-biased autism phenotypes in the proband pedigrees. One of these, a promoter variant, disrupts NFY binding and reduces MECP2 expression by ∼30%, a magnitude that produces social deficits, hyperactivity, and anxiety-like phenotypes in mice. These findings suggest noncoding MECP2 variants can cause idiopathic, male-biased autism and provide a framework for uncovering regulatory variants in other X chromosome neurodevelopmental genes that may contribute to autism's missing heritability.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147616","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,Marta Rodríguez-Balada,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.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.015","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"24 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090473","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":"Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I","authors":"Siying Lin,Seok-Ho Yu,Andrew C. Browning,Riccardo Sangermano,Andrzej B. Poplawski,Karolina M. Stepien,Peter Kiraly,Anna R. Ridgeway,Patrick Rump,Marianthi Karali,Francesca Simonelli,Laura K. Finnegan,G. Jane Farrar,Naomi Chadderton,Paul F. Kenna,Emma Duignan,Eleanor McCance,M. Dominik Fischer,Robin Lachmann,Yael Finezilber,Shaun M. Leo,Anthony G. Robson,Nishan Guha,Elaine Murphy,Sian Sperring,Kim Rodenburg,Aleksandr Jestin,Lonneke Haer-Wigman,Jan Willem R. Pott,Marlies M.B. Habing,Emily M. Place,Rachel M. Huckfeldt,Sandro Banfi,Marcela Votruba,Kinga M. Bujakowska,Heather Flanagan-Steet,Omar A. Mahroo,Andrew R. Webster,Susanne Roosing,Richard Steet,Gavin Arno","doi":"10.1016/j.ajhg.2026.09.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"176 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090474","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":"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":"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":"2165-2177"},"PeriodicalIF":7.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632940/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}