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Rare germline heterozygous missense variants of the BRCA1-Associated Protein 1 gene, BAP1, heterozygous missense variants cause a syndromic neurodevelopmental disorder

ABSTRACT: Nuclear deubiquitinase BAP1 (BRCA1-Associated Protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor gene whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a NDD or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder (NDD). Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired in matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190394 | GEO | 2021/12/10

REPOSITORIES: GEO

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