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De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.

ABSTRACT: The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.

SUBMITTER: Okur V 

PROVIDER: S-EPMC8651650 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.

Okur Volkan V   Chen Zefu Z   Vossaert Liesbeth L   Peacock Sandra S   Rosenfeld Jill J   Zhao Lina L   Du Haowei H   Calamaro Emily E   Gerard Amanda A   Zhao Sen S   Kelsay Jill J   Lahr Ashley A   Mighton Chloe C   Porter Hillary M HM   Siemon Amy A   Silver Josh J   Svihovec Shayna S   Fong Chin-To CT   Grant Christina L CL   Lerner-Ellis Jordan J   Manickam Kandamurugu K   Madan-Khetarpal Suneeta S   McCandless Shawn E SE   Morel Chantal F CF   Schaefer G Bradley GB   Berry-Kravis Elizabeth M EM   Gates Ryan R   Gomez-Ospina Natalia N   Qiu Guixing G   Zhang Terry Jianguo TJ   Wu Zhihong Z   Meng Linyan L   Liu Pengfei P   Scott Daryl A DA   Lupski James R JR   Eng Christine M CM   Wu Nan N   Yuan Bo B  

NPJ genomic medicine 20211207 1

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort  ...[more]

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