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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.

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Fig. 1: The genomic position and coding consequences of 14 different SETD1A variants.
Fig. 2: DNA fiber analysis to assess the impact of SETD1A variants.
Fig. 3: Clinical portrait photographs of patients with a SETD1A pathogenic variant.
Fig. 4: Mushroom body specific knockdown of Set1 causes defects in short- and long-term memory.

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Acknowledgements

We are grateful to all individuals and their parents for participating in this study. This work was supported by the Netherlands Organization for Health Research and Development (ZonMw grant 91718310) to TK, ERA-NET NEURON-102 SYNSCHIZ (grant 013-17-003 4538) to DS, Canadian Institutes of Health Research, Canadian Foundation for Innovation, and the Canada Research Chairs Program to JMK, MRC Career Development Fellowship (MR/P009085/1) and a University of Birmingham Fellowship to MRH. We thank the Bloomington Drosophila Stock Center at Indiana University for providing all Drosophila strains used in this study. Sequencing and analysis for patient 2 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141.

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Kummeling, J., Stremmelaar, D.E., Raun, N. et al. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0725-5

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