The H3-3A gene is located on chromosome 1 at 1q42.12 and encodes for a 135-amino acid protein named H3.3. H3.3 protein is a replication-independent variant of H3 histone that is expressed throughout the cell cycle. H3.3 supports chromosomal heterochromatic structures thus maintaining genome integrity during mammalian development and influences gene transcription/expression via post-translational modifications on histones. H3-3A was first reported in relation to autosomal dominant Bryant-Li-Bhoj neurodevelopmental syndrome 1 in 2020 (Bryant et al., PMID: 33268356). Bryant et al. demonstrated the presence of de novo heterozygous germline missense variants in H3-3A (n=33) or H3-3B (n=13) in a cohort of 46 unrelated patients (PMID: 33268356). These individuals have core phenotypes of neurologic dysfunction with brain anomalies and congenital anomalies with some individuals (5 of 33) with H3-3A variants showing progressive neurologic disease or regression. 25 unique missense variants have been reported in 35 patients, of which four are recurrent variants (p.Arg18Gly, p.Thr46Ile, p.Arg84Cys, p.Gln126Arg).
Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous missense variants in H3-3A were identified in at least 35 unrelated patients with clinical features suggestive of autosomal dominant Bryant-Li-Bhoj neurodevelopmental syndrome 1 (Maver et al 2019, PMID: 31942419; Bryant et al 2020, PMID: 33268356; Okur et al 2021, PMID: 34876591). This gene-disease association is supported by biochemical function, gene expression, protein interaction, non-human model organism (zebrafish) studies (Cox et al 2012, PMID: 23028350; Funk et al 2022, PMID:35930666; Di Liegro et al 2023, PMID:37446205; Tagami et al 2004, PMID: 14718166).
In summary, the H3-3A gene is definitively associated with autosomal dominant Bryant-Li-Bhoj neurodevelopmental syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 19, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.