American journal of human genetics最新文献

{"title":"A massively parallel reporter assay of MECP2 cis-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":"2254-2271"},"PeriodicalIF":7.7,"publicationDate":"2026-11-05","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":"This month in The Journal","authors":"Paul W. Hook,Alyson B. Barnes","doi":"10.1016/j.ajhg.2026.10.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.10.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149359716","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":"Scaling haplospecific antisense oligonucleotides from N-of-1 to broad use in genetic disease populations by diplotyping.","authors":"Olivia Kim-McManus, Pagé Goddard, Shahad Olsson, Liana Protopsaltis, Joseph Gleeson, Qing Zhang, Nafeesa Kahn, Ali Crawford, Stephen F Kingsmore","doi":"10.1016/j.ajhg.2026.08.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.017","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) are versatile disease-modifying therapies for genetic diseases. An accelerated US Food and Drug Administration (FDA) pathway enables ASO treatment trial initiation in an individual within a year. However, this rapid N-of-1 pathway lacks extensibility to broad use necessary for sustainability. Individualized ASOs bind pre-mRNAs encompassing an entire locus. Thus, ASOs targeting common heterozygous polymorphisms (SNPs) are potentially haplospecific in many individuals with dominant disorders. We developed haplospecific ASOs for two probands with SCN2A-complex neurodevelopmental disorder (CND) and gain-of-function (GOF) or mixed gain-loss dysfunction (GLD) variants. The ASOs targeted reference SCN2A intronic sequences containing SNPs. The probands each had SCN2A haplotypes with reference SNP alleles in cis with causal variants and alternate SNP alleles in cis with normal mRNA. Following N-of-1 demonstration of safety and efficacy, we evaluated their applicability to 21 SCN2A-CND probands using whole-genome sequencing (WGS) with haplotyping by read proximity. Ten (48%) probands had ASO-eligible diplotypes. Haplotype analysis of unrelated 1000 Genomes Project (1kGP) participants revealed 18 additional SCN2A haplotypes present in >20% of subjects, tagged by 156 SNPs. In silico assessment of specificity and potency identified additional haplospecific ASOs for validation in reprogrammed 1kGP cells heterozygous for the tagging SNPs. A combination of four haplospecific ASOs provided coverage for 76.2% of 1kGP subjects, potentially allowing scaling of N-of-1 FDA applications in future individuals with SCN2A-CND and GOF/GLD variants. Thus, population resources have potential to prepare haplospecific ASO therapies a priori for many persons and genetic diseases, with individual ASO selection by diagnostic WGS with haplotyping.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"113 11","pages":"2324-2341"},"PeriodicalIF":7.7,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340262","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 clinical diagnostics with interventional genetics for neurodevelopmental disorders.","authors":"Julia Macintosh, Khadijé Jizi, Ying Zhang, Charles-Olivier Martin, Malak Abuzgaya, Xin Zhang, Emily Ducharme, Andres Arriaga-Sierra, Huashan Peng, Anne-Marie Bélanger, Valérie K Fontaine, Chaoyi Gu, Anjie Ni, Basil Khan, Shaima Alsuwaidi, Peter Fleming, Amelia Semenak, Bavavarshini Tamilselvam, Yeqing Geng, Hooman Sadighian, Andrew G Ewing, Austen J Milnerwood, Guy A Rouleau, Jacques L Michaud, Sébastien Jacquemont, Carl Ernst","doi":"10.1016/j.ajhg.2026.09.006","DOIUrl":"10.1016/j.ajhg.2026.09.006","url":null,"abstract":"<p><p>Interventional genetics (IG) refers to the development of therapies aimed at treating the underlying genetic cause of disease. Diagnostic sequencing has advanced to the point where genetic results can be returned within weeks, meaning that therapeutically actionable variants associated with specific diseases could be developed immediately after diagnosis. Here, we describe 81 probands with a neurodevelopmental disorder (NDD) and family matched controls with full genotype/phenotype information and biobanked stem cells, most of which are consented for sharing. We outline a rapid and scalable pipeline for induced pluripotent stem cell (iPSC) generation directly from clinical collection, without the need for peripheral blood mononuclear cell (PBMC) storage, paired with induction to neurons. We provide a proof of principle for rapid creation of oligonucleotide therapeutics for Kleefstra syndrome. This work introduces a cohort of individuals with NDDs and an implemental pipeline to integrate IG with clinical diagnostics for NDDs. This information documents our experience and provides useful details for clinical centers interested in integrating IG for NDDs with diagnostic sequencing.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2310-2323"},"PeriodicalIF":7.7,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102914","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":"Recurrent de novo ABI2 p.Tyr491Cys variants define a neurodevelopmental syndrome with corpus callosum hypoplasia and white matter abnormalities","authors":"Emanuela Argilli,Caleb Yang,Carolyn Le,Hanna Retallack,Amanda M. Elashoff,Kendall Parks,Sonal Mahida,Heather Olson,Brian G. Skotko,Nancy Pinnell,James J. Dowling,Kimberly Amburgey,Louisa Kalsner,Deepa S. Rajan,Christine Munro,Christopher Barnett,Alicia B. Byrne,Eleina M. England,Erfan Aref-Eshghi,Sureni V. Mullegama,Michelle M. Morrow,Fadi F. Hamdan,Jacques L. Michaud,Elsa Rossignol,Zornitza Stark,Di Milnes,Alexis Bosman,Ruiji Jiang,Clare Bakker,Elizabeth George,Elliott H. Sherr","doi":"10.1016/j.ajhg.2026.10.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.10.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304810","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":"Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes","authors":"Konstantinos Tzoumkas,Gabriel T. Doctor,Omid Sadeghi-Alavijeh,Daniel P. Gale","doi":"10.1016/j.ajhg.2026.10.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.10.002","url":null,"abstract":"Monoallelic pathogenic or likely pathogenic variants in COL4A3 and COL4A4 occur in approximately 1 in 106 individuals, yet whether these paralogous genes confer equivalent pathogenicity for the same variant classes has not been tested at population scale. Using whole-genome sequencing data from the UK Biobank (UKB; n ≈ 500,000), with replication in the All of Us Research Program (n ≈ 414,000), we performed per-variant association testing, gene-based collapsing analyses, and phenome-wide association studies (PheWASs) across hematuria, proteinuria, and chronic kidney disease. We identified 64 COL4A3 and 92 COL4A4 rare variants significantly associated with hematuria or proteinuria, providing population-level quantitative evidence that may support variant interpretation. Glycine substitutions within collagenous domains conferred similar risks in both genes. In contrast, truncating and non-collagenous domain (NC1) missense variants were strongly associated with hematuria and proteinuria in COL4A4 heterozygotes but showed substantially attenuated or absent associations in COL4A3 heterozygotes despite comparable allele frequencies and predicted pathogenicity scores. These findings were independently replicated in All of Us. Genome-wide association analysis identified the COL4A3 and COL4A4 locus as the dominant genetic determinant of hematuria, attributable to the aggregate effects of rare coding variants with no evidence of independent common variant or trans-acting modifier effects. These findings demonstrate marked gene-specific differences in association with hematuria and proteinuria for truncating and NC1 variants between COL4A3 and COL4A4, challenging assumptions of equivalent pathogenicity across paralogous collagen IV genes. Gene identity, not variant class alone, should inform risk stratification, variant interpretation, and genetic counseling in collagen IV heterozygotes.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"8 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304806","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":"Deep CRISPR mutagenesis predicts cancer risk in Li-Fraumeni syndrome","authors":"Judith Penkert,Anika Großhennig,Christina M. Dutzmann,Annika Ewert,Rika Zimmer,Jan-Christoph Schoene-Bake,Valentina Moersch,Farina Silchmüller,Josephine Gieseke,Birte Sänger,Tanja Gerasimov,Christian P. Kratz","doi":"10.1016/j.ajhg.2026.09.016","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.09.016","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"9 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304807","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":"Functional stratification of YWHAZ variants explains distinct neurodevelopmental disorders.","authors":"Ivan K Popov, Marialetizia Motta, Ingrid Guarnetti Prandi, Jiahui Tao, Manuela Priolo, Marco Ferilli, Rami Abou Jamra, Elsa V Balton, Guillaume Banneau, Alessandro Bruselles, Krista Bukele, Cristel Chapel-Crespo, Giovanni Chillemi, Andrea Ciolfi, Viviana Cordeddu, Amy Crunk, Paola Daniele, Alessandro De Luca, Martine Doco-Fenzy, Ellen R Elias, Elisabetta Flex, Balram Gangaram, Kathryn Gasperian, Katheryn Grand, Deborah Holder, Sophie Julia, Eric Klee, Boris Keren, Chiara Leoni, Kathleen A Leppig, Cecilia Mancini, Monica Marica, Ieva Micule, Roberta Onesimo, Tilman Polster, Francesca Clementina Radio, Omar A Abdul-Rahman, Anita Rauch, Lisa A Schimmenti, Samantha A Schrier Vergano, Christina Szialta, Jeffrey Tenney, Martina Terrusa, Kathryn Nicole Weaver, Nancy William, Grace Yoon, Giuseppe Zampino, Chenbei Chang, Marco Tartaglia","doi":"10.1016/j.ajhg.2026.10.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.10.001","url":null,"abstract":"<p><p>The application of clinical genomics in personalized medical practice increasingly reveals that variants from single loci can lead to phenotypic heterogeneity. This necessitates functional characterization and classification of serial variants to correlate their associated clinical features and molecular properties. Recently, a few putative pathogenic variants in YWHAZ, encoding the 14-3-3ζ protein, have been implicated in clinically variable isolated and syndromic neurodevelopmental phenotypes, based on a few reported affected individuals, but the molecular basis of this heterogeneity has remained unclear. Here, we assembled a large cohort of individuals harboring de novo YWHAZ variants and categorized their clinical stratification into distinct neurodevelopmental conditions, including a typical presentation of cardiofaciocutaneous syndrome and a developmental and epileptic encephalopathy with sleep disorders. By integrating structural analyses, molecular dynamics simulations, in vitro biochemical and cell-based signaling studies, unbiased proteomics analysis, and in vivo phenotypic assays, we define distinct functional classes of pathogenic YWHAZ variants and establish robust genotype-phenotype correlations. We show that disease-associated YWHAZ variants differentially perturb 14-3-3ζ function by variably affecting protein abundance and binding to interacting partners, including the BRAF and RAF1 kinases. Notably, the recurrent p.Ser230Trp (c.689C>G) variant uniquely underlying cardiofaciocutaneous syndrome specifically enhances MAPK signaling, whereas other variants do not significantly impact signal flow through the cascade under the used experimental conditions. Our data establish a mechanistic framework linking allelic variation in YWHAZ to phenotypic heterogeneity.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149242585","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 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}