American journal of human genetics最新文献

{"title":"Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.","authors":"Marina Boon, Meghan R Mulligan, Jolijn J A Verseput, Barbara Šakić, Pleuni Schreurs, Mireia Coll-Tané, Andrea Accogli, Emily Alderman, Taryn Athey, Cornelius Boerkoel, Antonella Boni, Roseline Caumes, Erica Gerkes, Sabine Haase, Sylvie Jaillard, Lauren Jeffries, Peter Kannu, Monica Konstantino, Jonathan Lévy, Anna Lokchine, Maarten Massink, Nadra Nasser Samra, Renske Oegema, Marcello Scala, Jolanda Schieving, Sarina Schwartzmann, Henrike Lisa Sczakiel, Thomas Smol, Pasquale Striano, Alain Verloes, Amber Begtrup, Rolph Pfundt, Barbara Franke, Marieke Klein, Annette Schenck, Louise S Bicknell, Bert B A de Vries","doi":"10.1016/j.ajhg.2026.07.007","DOIUrl":"10.1016/j.ajhg.2026.07.007","url":null,"abstract":"<p><p>RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1853-1872"},"PeriodicalIF":7.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676870","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.2026.08.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"57 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877388","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":"All of Us Research Program year in review: 2025","authors":"Tara Dutka,Jennifer Adjemian,Hristina Denic-Roberts,Erika J. Faust,Elyse Kozlowski,Minnkyong Lee,Xia M. Lin,Grace F. Liou,Sana H. Mian,Nguyen Park,Katrina Theisz,Yanqin Yang,Geoffrey S. Ginsburg","doi":"10.1016/j.ajhg.2026.08.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"185 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877390","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":"Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk","authors":"Olivier Quenez,Catherine Schramm,Kévin Cassinari,Aude Nicolas,Joan Groeneveld,Guillaume Huguet,Benjamin Grenier-Boley,Marc Hulsman,G. Bragi Walters,Itziar de Rojas,Anne Rovelet-Lecrux,Sébastien Feuillette,Laetitia Miguel,Anne-Claire Richard,Stéphane Rousseau,Shahzad Ahmad,Najaf Amin,Philippe Amouyel,Olivia Belbin,Céline Bellenguez,Claudine Berr,Paola Bossù,Femke Bouwman,Jose Bras,Jordi Clarimon,Antonio Daniele,Jean-François Dartigues,Stéphanie Debette,Jean-François Deleuze,Nicola Denning,Oriol Dols-Icardo,Cornelia M. van Duijn,Juan Fortea,Nick C. Fox,Ruth Frikke-Schmidt,Daniela Galimberti,Roberta Ghidoni,Vilmantas Giedraitis,Johan J.P. Gille,Detelina Grozeva,Rita Guerreiro,Edna Grünblatt,John Hardy,Steffi G. Riedel-Heller,Mikko Hiltunen,Clive Holmes,Jakub Hort,Holger Hummerich,M. Arfan Ikram,M. Kamran Ikram,Martin Ingelsson,Iris E. Jansen,Amit Kawalia,Robert Kraaij,Patrick G. Kehoe,Marc Lathrop,Morgane Lacour,Afina W. Lemstra,Alberto Lleó,Lauren Luckcuck,Marcel M.A.M. Mannens,Rachel Marshall,Carlo Masullo,Simon Mead,Patrizia Mecocci,Alexandre de Mendonça,Alun Meggy,Shima Mehrabian,Merel O. Mol,Kevin Morgan,Alexandre Morin,Benedetta Nacmias,Penny J. Norsworthy,Robert Olaso,Florence Pasquier,Pau Pastor,Fabrizio Piras,Julius Popp,Alfredo Ramirez,Rachel Raybould,Richard Redon,Marcel J.T. Reinders,Fernando Rivadeneira,Jeroen G.J. van Rooij,Natalie S. Ryan,Salha Saad,Pascual Sanchez-Juan,Nikolaos Scarmeas,Philip Scheltens,Jonathan M. Schott,Davide Seripa,Daoud Sie,Rebecca Sims,Erik A. Sistermans,Sandro Sorbi,Kristel Sleegers,Resie van Spaendonk,John C. van Swieten,Niccolo’ Tesi,Betty M. Tijms,Magda Tsolaki,André G. Uitterlinden,Jort Vijverberg,Pieter Jelle Visser,Michael Wagner,Julie Williams,Aline Zarea,EADB Consortium,Emmanuelle Génin,Henne Holstege,Daniel F. Gudbjartsson,David Wallon,Magalie Lecourtois,Maria Victoria Fernandez,Hreinn Stefansson,Sébastien Jacquemont,Jean-Charles Lambert,Sven J. van der Lee,Camille Charbonnier,Gaël Nicolas","doi":"10.1016/j.ajhg.2026.07.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.013","url":null,"abstract":"Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10−7). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"13 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821586","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":"Shared genetic basis and structure of syndromic and normal facial variation","authors":"J. David Aponte,Cassidy Da Silva,Hanne Hoskens,Seppe Goovaerts,Michiel Vanneste,Jay Devine,Katherine Caine,Alexander Buchner Beaudet,H. Artee Luchman,Seth M. Weinberg,Hilde Peeters,Ophir D. Klein,Ralph S. Marcucio,A. Micheil Innes,Peter Claes,Richard A. Spritz,Francois P. Bernier,Benedikt Hallgrímsson","doi":"10.1016/j.ajhg.2026.07.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.014","url":null,"abstract":"The question of how gene mutations of large effect and common variants of small effect relate to phenotypic variation dates from the origins of genetics. Mendelian diseases result from rare germline variants with major effects, while complex traits are associated with multiple, mostly common variants of small effect. High-dimensional phenotypes, such as facial shape, can shed new light on this age-old dichotomy, as their variation can be characterized in terms of directions in multivariate morphospace. Within such spaces, do Mendelian disease mutations move phenotypes along the same directions as common variants, or do they forge new directions that diverge from the common structure of background variation? Here, we analyze facial shape variation for 66 syndromes, quantify multivariate axes of facial shape variation for each syndrome, and test whether common genetic variants in cohorts of non-syndromic subjects are associated with phenotypic position along these same axes. We find that syndromic facial shape generally follows the background variance-covariance structure of facial shape in the general population. Furthermore, syndromic probands’ unaffected relatives have subtle facial morphology resembling the syndromes of their affected relatives. These results suggest that Mendelian disease variants act on facial shape in ways similar to common variants. Syndromic probands with higher “severity” likely occur on genetic backgrounds with higher cumulative severity of common variants for each syndromic axis. These findings position Mendelian diseases at extremes along phenotypic continua that exist in the background population rather than as qualitatively different phenotypes distinct from the overall structure of normal human phenotypic variation.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"64 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768870","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":"Overlapping Xp21.2 duplications define an X-linked hypotrichosis simplex and implicate TAB3 dosage sensitivity","authors":"Qiaoyu Cao, Anqi Zhao, Jianbo Wang, Xinjie Lin, Zhoukai Long, Chaolan Pan, Kai Yang, Chun Gu, Yumeng Wang, Lu Li, Xiaoxiao Wang, Jinran Lin, Wenyu Wu, Rushan Xia, Ming Li","doi":"10.1016/j.ajhg.2026.08.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.08.009","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"15 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754745","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":"Examining gaps in institutional policies for clinical genomic data sharing: A cross-jurisdictional study","authors":"Zhaoping Ju, Yunhe Xue, Abby Rud, Juliann M. Savatt, Jordan Lerner-Ellis, Heidi L. Rehm, Yann Joly, Diya Uberoi","doi":"10.1016/j.ajhg.2026.07.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.012","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"5 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754751","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 Gabriella Miller Kids First Data Resource for genomic research in pediatric cancer and congenital anomalies","authors":"David M. Higgins, Christopher Blackden, Miguel Brown, Christina Diaz, Leslie Duffy, Christopher Friedman, Yiran Guo, Mateusz Koptyra, Qi Li, Alex Lubneuski, Dan Miller, Bobby Moulder, Wendy Payton, Emily Reed, Whitney Rife, Alex Sickler, Natasha Singh, Amanda Warkow, Eric Wenger, Jessica Wong, Bo Zhang, Chuwei Zhong, Yuankun Zhu, Gaelle Altefrohne, Denis Beauregard, Jeremy Costanza, Evans Girard, Luc-Frederic Langis, Lucas Lemonnier, Adrian Paul, Céline Pelletier, Karine St-Onge, Jean-Philippe Thibert, Michele Mattioni, Surya Saha, Jared Rozowsky, Milos Trboljevac, Marko Zecevic, Jeff Knight, Gina Kuffel, Radhika Reddy, Pauline Ribeyre, Bailey Farrow, Yelena Cox, Andrew Ericson, Jamed Ferreris Vargas, Sophie Forman, Sofia Labrecque, Eric Torstenson, Kai Yin Ho, Nicole A. Vasilevsky, Emily Boja, Valerie Cotton, Danielle Daee, Marcia V. Fournier, Jaime M. Guidry Auvil, Andréa C. Harris, Huiqing Li, Lu Wang, Brandi Davis-Dusenbery, Melissa A. Haendel, Jena Lilly, Phillip B. Storm, Sam Volchenboum, Robert L. Grossman, Robert Carroll, Jack DiGiovanna, Deanne Taylor, Vincent Ferretti, Adam Resnick, Allison P. Heath","doi":"10.1016/j.ajhg.2026.07.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.010","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"24 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754746","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":"Shared inheritance reveals landscape of somatic and germline cancer risk in TP53","authors":"Hamish A.J. MacGregor, Jamie R. Blundell, Douglas F. Easton","doi":"10.1016/j.ajhg.2026.07.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.011","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"12 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754747","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":"Anthropometric and cardio-metabolic trait variation and genetic associations in sub-Saharan Africa","authors":"Matthew E.B. Hansen, Ujani Hazra, Michelle Kim, Srilakshmi M. Raj, Shaohua Fan, William Beggs, Sunungouko Wata Mpoloka, Gaonyadiwe George Mokone, Thomas Nyambo, Dawit Wolde Meskel, Gurja Belay, Jibril Hirbo, Alessia Ranciaro, Joseph Lachance, Sarah A. Tishkoff","doi":"10.1016/j.ajhg.2026.07.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2026.07.006","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148715624","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}