Document Type

Article

Publication Date

11-2023

Identifier

DOI: 10.1016/j.gim.2023.100950

Abstract

PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.

METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.

RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD.

CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.

Journal Title

Genetics in medicine : official journal of the American College of Medical Genetics

Volume

25

Issue

11

First Page

100950

Last Page

100950

MeSH Keywords

Humans; Abnormalities, Multiple; Face; Micrognathism; Intellectual Disability; Facies; Neurodevelopmental Disorders; Phenotype; DNA-Binding Proteins; Transcription Factors

Keywords

BAF; BAFopathy; Coffin-Siris syndrome; NDD; SMARCC2

Comments

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Publisher's Link: https://www.gimjournal.org/article/S1098-3600(23)00963-2/fulltext

Download

Share

COinS