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

TitleDe novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.
Publication TypeJournal Article
Year of Publication2021
AuthorsOkur, V, Chen, Z, Vossaert, L, Peacock, S, Rosenfeld, J, Zhao, L, Du, H, Calamaro, E, Gerard, A, Zhao, S, Kelsay, J, Lahr, A, Mighton, C, Porter, HM, Siemon, A, Silver, J, Svihovec, S, Fong, C-T, Grant, CL, Lerner-Ellis, J, Manickam, K, Madan-Khetarpal, S, McCandless, SE, Morel, CF, G Schaefer, B, Berry-Kravis, EM, Gates, R, Gomez-Ospina, N, Qiu, G, Zhang, TJianguo, Wu, Z, Meng, L, Liu, P, Scott, DA, Lupski, JR, Eng, CM, Wu, N, Yuan, B
JournalNPJ Genom Med
Volume6
Issue1
Pagination104
Date Published2021 Dec 07
ISSN2056-7944
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.

DOI10.1038/s41525-021-00268-8
Alternate JournalNPJ Genom Med
PubMed ID34876591
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
UM1HG006542 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) /
FRN: 135790 / / Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre) /
81772301 and 81972132 / / National Natural Science Foundation of China (National Science Foundation of China) /
81930068 and 81772299 / / National Natural Science Foundation of China (National Science Foundation of China) /
81822030 and 82072391 / / National Natural Science Foundation of China (National Science Foundation of China) /
2020-I2M-C&T-B-030 / / Chinese Academy of Medical Sciences (CAMS) /
2019PT320025 / / Chinese Academy of Medical Sciences (CAMS) /
7191007 / / Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation) /
JQ20032 / / Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation) /