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

Abstract

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.

• Authors: Joost Kummeling, Diante E Stremmelaar, Nicholas Raun, Margot R F Reijnders, Marjolein H Willemsen, Martina Ruiterkamp-Versteeg, Marga Schepens, Calvin C O Man, Christian Gilissen, Megan T Cho, Kirsty McWalter, Margje Sinnema, James W Wheless, Marleen E H Simon, Casie A Genetti, Alicia M Casey, Paulien A Terhal, Jasper J van der Smagt, Koen L I van Gassen, Pascal Joset, Angela Bahr, Katharina Steindl, Anita Rauch, Elmar Keller, Annick Raas-Rothschild, David A Koolen, Pankaj B Agrawal, Trevor L Hoffman, Nina N Powell-Hamilton, Isabelle Thiffault, Kendra Engleman, Dihong Zhou, Olaf Bodamer, Julia Hoefele, Korbinian M Riedhammer, Eva M C Schwaibold, Velibor Tasic, Dirk Schubert, Deniz Top, Rolph Pfundt, Martin R Higgs, Jamie M Kramer, Tjitske Kleefstra
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 26 Issue 6 Pg. 2013-2024 (06 2021) ISSN: 1476-5578 [Electronic] England
• PMID: 32346159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Histone-Lysine N-Methyltransferase
• Setd1A protein, human

Topics

• Animals
• Child
• Drosophila
• Drosophila melanogaster
• Haploinsufficiency (genetics)
• Histone-Lysine N-Methyltransferase (genetics)
• Humans
• Intellectual Disability (genetics)
• Neurodevelopmental Disorders (genetics)