Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 6, Pages 2013-2024Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-020-0725-5
Keywords
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Funding
- Netherlands Organization for Health Research and Development (ZonMw grant) [91718310]
- ERA-NET NEURON-102 SYNSCHIZ [013-17-003 4538]
- Canadian Institutes of Health Research
- Canadian Foundation for Innovation
- Canada Research Chairs Program
- MRC Career Development Fellowship [MR/P009085/1]
- University of Birmingham Fellowship
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute [UM1 HG008900]
- National Human Genome Research Institute [R01 HG009141]
- MRC [MR/P009085/1] Funding Source: UKRI
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Mutations in histone methyltransferases (HMTs), such as SETD1A, are major contributing factors in neurodevelopmental disorders (NDDs). Identifying clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A, this study found that individuals with SETD1A variants present with global developmental delay, intellectual disability, facial dysmorphisms, behavioral and psychiatric problems. Patient-derived cell lines with SETD1A variants showed DNA damage repair defects, suggesting these variants act as loss-of-function alleles. The study also revealed the importance of SETD1A in postmitotic neurons for normal memory function in Drosophila melanogaster, indicating a role in post development neuronal processes and cognitive functioning.
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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