Delineating the molecular and phenotypic spectrum of theSETD1B-related syndrome

Abstract

Pathogenic 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 eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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. Our 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. Interestingly, 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. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Case Report: Two New Cases of Chromosome 12q14 Deletions and Review of the Literature

“…In the case of individual 2, the initial diagnosis of a 12q13.2q14.2 deletion was made years before SMARCC2 was identified as a disease gene. Similarly, re-interpretation and additional fine mapping of previously suggested microdeletion syndromes at 12q15 and 12q24.31 has now led to the conclusions that most of the phenotypes associated with these microdeletion syndromes are caused by alterations of the genes CNOT2 (Alesi et al, 2017 ) and SETD1B (Weerts et al, 2021 ), respectively. It is expected that further progress in genetics, cell biology and personalized medicine will advance options to influence the phenotypes by gene-specific or pathway driven therapeutics.…”