Abstract
PurposePathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. MethodsWe perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. ResultsOur data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. ConclusionInsights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
Highlights
SETD1B encodes a lysine-specific histone methyltransferase that methylates histone H3 at position lysine-4 (H3K4me1, H3K4me2, H3K4me3) as part of a multisubunit complex known as COMPASS [1, 2]
We report on the molecular and phenotypic spectrum of 36 individuals with sequence variants in SETD1B, representing the largest cohort reported to date
The emerging phenotype of SETD1B-associated disorder consists of global developmental delay, language delay including regression, intellectual disability, autism, and epilepsy
Summary
SETD1B encodes a lysine-specific histone methyltransferase that methylates histone H3 at position lysine-4 (H3K4me, H3K4me, H3K4me3) as part of a multisubunit complex known as COMPASS [1, 2]. The SETD1B protein consists of 1,966 amino acids and has several (presumed) functional domains (Fig. 1). At the C-terminus, SETD1B harbors a catalytic SET domain crucial for histone methyltransferase activity, bordered proximally by the N-SET domain including a conserved WDR5-interacting (WIN) motif [6], and distally by the post-SET domain. H3K4me is enriched at promoter and transcription start sites whereas H3K4me and H3K4me are enriched at enhancer sites, being associated with active gene transcription and euchromatin [7]. Epigenetic changes have been observed in both animal models and patient material [8,9,10] at promoters and intergenic regions, confirming that SETD1B epigenetically controls gene expression and chromatin state. SETD1B is constrained for both missense and loss-of-function variants [11]
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