Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Layo-Carris DE, Lubin EE, Sangree AK, Clark KJ, Durham EL, Gonzalez EM, Smith S, Angireddy R, Wang XM, Weiss E, Mendoza-Londono R, Dupuis L, Damseh N, Velasco D, Valenzuela I, Codina-Solà M, Ziats C, Have J, Clarkson K, Steel D, Kurian M, Barwick K, Carrasco D, Dagli AI, Nowaczyk MJ, Hančárová M, Bendová Š, Prchalova D, Sedláček Z, Baxová A, Nowak CB, Douglas J, Chung WK, Longo N, Platzer K, Klöckner C, Averdunk L, Wieczorek D, Krey I, Zweier C, Reis A, Balci T, Simon M, Kroes HY, Wiesener A, Vasileiou G, Marinakis NM, Veltra D, Sofocleous C, Kosma K, Traeger Synodinos J, Voudris KA, Vuillaume ML, Gueguen P, Derive N, Colin E, Battault C, Au B, Delatycki M, Wallis M, Gallacher L, Majdoub F, Smal N, Weckhuysen S, Schoonjans AS, Kooy RF, Meuwissen M, Cocanougher BT, Taylor K, Pizoli CE, McDonald MT, James P, Roeder ER, Littlejohn R, Borja NA, Thorson W, King K, Stoeva R, Suerink M, Nibbeling E, Baskin S, L. E. Guyader G, Kaplan J, Muss C, Carere DA, Bhoj EJ, Bryant LM (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1038/s41431-024-01610-1

Abstract

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 Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals.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.

Authors with CRIS profile

Involved external institutions

Children's Hospital of Philadelphia United States (USA) (US) Greenwood Genetic Center United States (USA) (US) University College London (UCL) United Kingdom (GB) Cook Children's Medical Center United States (USA) (US) Orlando Health Arnold Palmer Hospital for Children United States (USA) (US) Hamilton Health Sciences (HHS) Canada (CA) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) General University Hospital in Prague / Všeobecná Fakultní Nemocnice v Praze (VFN) Czech Republic (CZ) Massachusetts General Hospital United States (USA) (US) Veterans Affairs Healthcare System Boston and Harvard Medical School United States (USA) (US) University of Utah United States (USA) (US) Universität Leipzig Germany (DE) Heinrich-Heine-Universität Düsseldorf Germany (DE) National and Kapodistrian University of Athens Greece (GR) Murdoch Childrens Research Institute Australia (AU) Tasmanian Department of Health Australia (AU) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Hospital Network Antwerp / Ziekenhuis Netwerk Antwerpen (ZNA) Belgium (BE) Duke University Health System United States (USA) (US) The Hospital for Sick Children (SickKids) Canada (CA) University of Nebraska Medical Center (UNMC) United States (USA) (US) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Shodair Children's Hospital United States (USA) (US) Western University Canada (CA) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Baylor College of Medicine United States (USA) (US) University of Miami United States (USA) (US) Multicare Health System United States (USA) (US) Centre Hospitalier Le Mans France (FR) Leiden University Medical Center Netherlands (NL) Centre Hospitalier Régional Universitaire de Tours France (FR) GCS SeqOIA France (FR) Centre hospitalier universitaire (CHU) d'Angers France (FR) University of Calgary Canada (CA) DMG Children's Rehabilitative Services United States (USA) (US) Centre hospitalier universitaire de Poitiers (CHU de Poitiers) France (FR) Nemours Children's Hospital United States (USA) (US) GeneDX United States (USA) (US)

How to cite

APA:

Layo-Carris, D.E., Lubin, E.E., Sangree, A.K., Clark, K.J., Durham, E.L., Gonzalez, E.M.,... Bryant, L.M. (2024). Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals. European Journal of Human Genetics. https://doi.org/10.1038/s41431-024-01610-1

MLA:

Layo-Carris, Dana E., et al. "Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals." European Journal of Human Genetics (2024).

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