20.500.12556/DiRROS-29706 MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature 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 MSL2 male-specific lethal complex neurodevelopmental syndrome epigenetics autism epilepsy connective tissue episignature iPSC true false true Angleški jezik Ni določen Na pristajalni strani članka navedeno: "User License: Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)." (https://doi.org/10.1016/j.ajhg.2024.05.001, 3. 6. 2026) Neznano 2026-06-03 12:50:51 2026-06-03 12:50:51 2026-06-04 04:04:42 0000-00-00 00:00:00 2024 0 0 Nasl. z nasl. zaslona; Opis z dne 12. 7. 2024; str. 1330-1351 iss. 7 Vol. 111 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 575 1537-6605 10.1016/j.ajhg.2024.05.001 201711107 RAZ_Karayol_Remzi_2024.pdf RAZ_Karayol_Remzi_2024.pdf 1 565A500DAC83475906EE0216866BBAEC 198e236cd674d8dea2e9a305258e5eed3b980aec66bda9bc89f0f9a449c88bb6 184e8afa-5f3b-11f1-9215-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=44626 https://www.cell.com/ajhg/fulltext/S0002-9297(24)00164-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0002929724001642%3Fshowall%3Dtrue#%20 1 17d5dcfe-5f3a-11f1-9215-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=44623 Univerzitetni klinični center Ljubljana 0 0 0