MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature

Karayol R, Borroto MC, Haghshenas S, Namasivayam A, Reilly J, Levy MA, Relator R, Kerkhof J, McConkey H, Shvedunova M, Petersen AK, Magnussen K, Zweier C, Vasileiou G, Wiesmann da Silva Reis A, Savatt JM, Mulligan MR, Bicknell LS, Poke G, Abu-El-Haija A, Duis J, Hannig V, Srivastava S, Barkoudah E, Hauser NS, van den Born M, Hamiel U, Henig N, Baris Feldman H, McKee S, Krapels IP, Lei Y, Todorova A, Yordanova R, Atemin S, Rogac M, McConnell V, Chassevent A, Barañano KW, Shashi V, Sullivan JA, Peron A, Iascone M, Canevini MP, Friedman J, Reyes IA, Kierstein J, Shen JJ, Ahmed FN, Mao X, Almoguera B, Blanco-Kelly F, Platzer K, Treu AB, Quilichini J, Bourgois A, Chatron N, Januel L, Rougeot C, Carere DA, Monaghan KG, Rousseau J, Myers KA, Sadikovic B, Akhtar A, Campeau PM (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 111

Pages Range: 1330-1351

Journal Issue: 7

DOI: 10.1016/j.ajhg.2024.05.001

Abstract

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Authors with CRIS profile

Involved external institutions

Plovdiv Medical University / Медицински университет в Пловдив Bulgaria (BG) University of Otago New Zealand (NZ) Legacy Emanuel Medical Center United States (USA) (US) Maastricht University Netherlands (NL) University of Colorado Anschutz Medical Campus United States (USA) (US) Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics Germany (DE) Tel Aviv University Israel (IL) Erasmus University Medical Center (MC) Netherlands (NL) London Health Sciences Centre Canada (CA) Johns Hopkins Hospital United States (USA) (US) Universität Leipzig Germany (DE) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) Hospital Universitario Fundación Jiménez Díaz Spain (ES) Université Sorbonne Paris Cité France (FR) Western University Canada (CA) Duke University United States (USA) (US) University of California, Davis (UC Davis, UCD) United States (USA) (US) Vanderbilt University United States (USA) (US) Tel Aviv Sourasky Medical Center / Ichilov Hospital Israel (IL) Hunan Provincial Maternal and Child Health Hospital / 湖南省妇幼保健院 China (CN) Meyer Children’s Hospital Italy (IT) Hospices Civils de Lyon (CHU) France (FR) Baylor College of Medicine United States (USA) (US) Boston Children's Hospital United States (USA) (US) Genetic Health Service NZ New Zealand (NZ) Azienda Ospedaliera Papa Giovanni XXIII Italy (IT) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH Germany (DE) Rady Children's Hospital San Diego United States (USA) (US) Inova Fairfax Hospital (IFH) United States (USA) (US) Biologie, Génétique et Thérapies ostéoArticulaires et Respiratoires (BioTARGen) France (FR) Belfast City Hospital / Ospidéal Chathair Bhéal Feirste United Kingdom (GB) Harvard University United States (USA) (US) Kennedy Krieger Institute United States (USA) (US) GeneDX United States (USA) (US) Geisinger Health System United States (USA) (US) Medical University Sofia / Медицински университет Bulgaria (BG)

How to cite

APA:

Karayol, R., Borroto, M.C., Haghshenas, S., Namasivayam, A., Reilly, J., Levy, M.A.,... Campeau, P.M. (2024). MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature. American Journal of Human Genetics, 111(7), 1330-1351. https://doi.org/10.1016/j.ajhg.2024.05.001

MLA:

Karayol, Remzi, et al. "MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature." American Journal of Human Genetics 111.7 (2024): 1330-1351.

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