Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder

Chromatin regulation is critical for neurodevelopment, and its disruption has emerged as a key pathogenic mechanism in neurodevelopmental disease, including autism spectrum disorder (ASD), a condition known for genetic and phenotypic heterogeneity. We previously identified an ASD gene, KDM5A, encoding a histone H3 lysine 4 demethylase, and reported de novo and inherited variants in nine individuals with severe ASD and other neurodevelopmental phenotypes. Here, we expand the genetic and phenotypic spectrum of KDM5A-related neurodevelopmental disorders and investigate the functional impact of identified variants. Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features. The variants include missense, nonsense, frameshift, and splice site, distributed across nearly all functional domains of the protein. Structural modeling revealed localized conformational disruptions, particularly at conserved residues in enzymatic or chromatin-interacting domains. For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals. Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin binding motif and the Jumonji C domain of the enzymatic core. American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic. Together, these findings implicate diverse KDM5A alleles in a rare but recurrent form of ASD, and establish KDM5A as a key regulator of neurodevelopment and chromatin-mediated ASD pathogenesis.

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Journal
Human Genetics and Genomics Advances
Published
2026-03-01
DOI
https://doi.org/10.1016/j.xhgg.2026.100594
Primary Topic
Autism Spectrum Disorder Research
Type
article
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article

Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder

Mahya Ebrahimi Nasab, Zahra Firoozfar, Kiran Kaur, Vinod K. Misra et al.
Human Genetics and Genomics Advances
Autism Spectrum Disorder Research
article

Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder

Mahya Ebrahimi Nasab, Zahra Firoozfar, Kiran Kaur, Vinod K. Misra, Milen Velinov, Sahar Sedighzadeh, Lailá Bastaki, Mina Zamani, Karl Kavanagh, Ivan P. Ivanovski, Berten Ceulemans, Seyed Ali Madani Manshadi, Cécile Courdier, Meghan N. Bartos, Reem M. Elshafie, Maria H. Chahrour, Lauretta El Hayek, Tanja Frey, Paula Goldenberg, Lewis Pang, Anna C.E. Hurst, Majid Mojarrad, Michael Day, Atieh Eslahi, Kristof Van Schil, Katie O’Connor, Vincent Michaud, Ashlesha Gogate, Leeran Dublin-Ryan, A. Weber, Anita Rauch, Susan M. Hiatt, Maha S. Zaki, Matthias De Wachter, Carsten Bergmann, Reza Maroofian, Servi J.C. Stevens, Eduardo Humberto Sanchez-Mendoza, Charles DeLuca, Mehran Beiraghi Toosi, Dor Mohammad Kordi-Tamandani, Henry Houlden, Ali Khajeh, Wei-Chen Chen, Janna Kenny, Daniel C. Koboldt, Xiaoming Shen, Etienne J.M. Janssen, Katharina Steindl, Dana Marafi, Masoomeh Ale Rasoul, Denisa Weis, Henri Margot
article en

Abstract

Chromatin regulation is critical for neurodevelopment, and its disruption has emerged as a key pathogenic mechanism in neurodevelopmental disease, including autism spectrum disorder (ASD), a condition known for genetic and phenotypic heterogeneity. We previously identified an ASD gene, KDM5A, encoding a histone H3 lysine 4 demethylase, and reported de novo and inherited variants in nine individuals with severe ASD and other neurodevelopmental phenotypes. Here, we expand the genetic and phenotypic spectrum of KDM5A-related neurodevelopmental disorders and investigate the functional impact of identified variants. Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features. The variants include missense, nonsense, frameshift, and splice site, distributed across nearly all functional domains of the protein. Structural modeling revealed localized conformational disruptions, particularly at conserved residues in enzymatic or chromatin-interacting domains. For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals. Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin binding motif and the Jumonji C domain of the enzymatic core. American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic. Together, these findings implicate diverse KDM5A alleles in a rare but recurrent form of ASD, and establish KDM5A as a key regulator of neurodevelopment and chromatin-mediated ASD pathogenesis.

Human Genetics and Genomics Advances
University College Dublin (IE), Rutgers, The State University of New Jersey (US), Yazd University (IR), Shahed University (IR), Johannes Kepler University of Linz (AT), Nationwide Children's Hospital (US), Royal College of Surgeons in Ireland (IE), University of Antwerp (BE), Université de Bordeaux (FR), Inserm (FR), Central Michigan University (US), Mashhad University of Medical Sciences (IR), University of Shahrood (IR), University of Sistan and Baluchestan (IR), University of Zurich (CH), Royal Devon & Exeter NHS Foundation Trust (GB), Maastricht University Medical Centre (NL), Johnson University (US), Centre Hospitalier Universitaire de Bordeaux (FR), University of Alabama at Birmingham (US), Kuwait University (KW), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Southwestern Medical Center (US), University Hospital of Zurich (CH), Antwerp University Hospital (BE), Bordeaux Population Health (FR), Institute of Human Genetics (PL), Kepler Universitätsklinikum (AT), University Children's Hospital Zurich (CH), Ministry of Health (KW), Children's Hospital of Michigan (US), Zahedan University of Medical Sciences (IR), HudsonAlpha Institute for Biotechnology (US), National Hospital for Neurology and Neurosurgery (GB), Ghaem Hospital (IR), University College London (GB), The University of Texas Southwestern Medical Center (US)
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Autism Spectrum Disorder Research
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