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


DOI: 10.1038/s41431-024-01610-1


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 Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals.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

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

How to cite


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


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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