Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals
Authors: Layo-Carris Dana E. , Lubin Emily E. , Sangree Annabel K. , Clark Kelly J. , Durham Emily L. , Gonzalez Elizabeth M. , Smith Sarina , Angireddy Rajesh , Wang Xiao Min , Weiss Erin , Toutain Annick , Mendoza-Londono Roberto , Dupuis Lucie , Damseh Nadirah , Velasco Danita , Valenzuela Irene , Codina-Solà Marta , Ziats Catherine , Have Jaclyn , Clarkson Katie , Steel Dora , Kurian Manju , Barwick Katy , Carrasco Diana , Dagli Aditi I. , Nowaczyk M. J. M. , Hančárová Miroslava , Bendová Šárka , Prchalova Darina , Sedláček Zdeněk , Baxová Alica , Nowak Catherine Bearce , Douglas Jessica , Chung Wendy K. , Longo Nicola , Platzer Konrad , Klöckner Chiara , Averdunk Luisa , Wieczorek Dagmar , Krey Ilona , Zweier Christiane , Reis Andre , Balci Tugce , Simon Marleen , Kroes Hester Y. , Wiesener Antje , Vasileiou Georgia , Marinakis Nikolaos M. , Veltra Danai , Sofocleous Christalena , Kosma Konstantina , Traeger Synodinos Joanne , Voudris Konstantinos A. , Vuillaume Marie-Laure , Gueguen Paul , Derive Nicolas , Colin Estelle , Battault Clarisse , Au Billie , Delatycki Martin , Wallis Mathew , Gallacher Lyndon , Majdoub Fatma , Smal Noor , Weckhuysen Sarah , Schoonjans An-Sofie , Kooy R. Frank , Meuwissen Marije , Cocanougher Benjamin T. , Taylor Kathryn , Pizoli Carolyn E. , McDonald Marie T. , James Philip , Roeder Elizabeth R. , Littlejohn Rebecca , Borja Nicholas A. , Thorson Willa , King Kristine , Stoeva Radka , Suerink Manon , Nibbeling Esther , Baskin Stephanie , L. E. Guyader Gwenaël , Kaplan Julie , Muss Candace , Carere Deanna Alexis , Bhoj Elizabeth J. K. , Bryant Laura M. 
Published: April 2024

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1–4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1–4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.