Journal Article

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Simon Marleen E H, Kummeling Joost, Sinnema Margje, Cho, Megan T, Higgs, Martin R, Zhou Dihong, Casey, Alicia M, Agrawal, Pankaj B, McWalter Kirsty, Joset Pascal, Schwaibold Eva M C, Raun, Nicholas, Schepens Marga, Engleman Kendra, Genetti, Casie A, Bahr, Angela, Thiffault Isabelle, Willemsen, Marjolein H, Kramer, Jamie M, Powell-Hamilton, Nina N, Keller, Elmar, Ruiterkamp-Versteeg Martina, Rolph, Pfundt, Wheless, James W, Tasic Velibor, Schubert, Dirk, Bodamer Olaf, Top Deniz, Reijnders Margot R F, Rauch, Anita, Koolen David A, Man Calvin C O, van Gassen Koen L I, Raas-Rothschild Annick, van der Smagt Jasper J, Hoffman, Trevor L, Kleefstra Tjitske, Gilissen, Christian, Steindl Katharina, Terhal, Paulien A, Hoefele Julia, Riedhammer, Korbinian M, Stremmelaar, Diante E

2021

Overview

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

• Publisher: Nature Publishing Group
• Subject: Cell cycle / Cell differentiation / Cognitive ability / DNA damage / DNA repair / Haploinsufficiency / Hereditary diseases / Histone H3 / Histones / Insects / Intellectual disabilities / Lymphoblastoid cell lines / Lysine / Mental disorders / Microencephaly / Neural stem cells / Neurodevelopmental disorders / Patients / Pediatrics / Phenotypes / Progenitor cells / RNA-mediated interference / Schizophrenia