Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

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Genomics England Res , Weerts , M J A , Lanko , K , Järvelä , I & Lauronen , L 2021 , ' Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome ' , Genetics In medicine , vol. 23 , no. 11 , pp. 2122-2137 .

Title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome
Author: Genomics England Res; Weerts, Marjolein J. A.; Lanko, Kristina; Järvelä, Irma; Lauronen, Leena
Contributor organization: Irma Järvelä / Principal Investigator
Department of Medical and Clinical Genetics
HUS Medical Imaging Center
BioMag Laboratory
HUS Children and Adolescents
Kliinisen neurofysiologian yksikkö
Date: 2021-11
Language: eng
Number of pages: 16
Belongs to series: Genetics In medicine
ISSN: 1098-3600
Abstract: Purpose 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 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. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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. Results 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. 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. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
3124 Neurology and psychiatry
3111 Biomedicine
3112 Neurosciences
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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