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 Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals.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

2nd Department of Paediatrics University of Athens 'P and A Kyriakou' Children's Hospital Athens Greece

Applied and Translational Neurogenomics Group Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Applied and Translational Neurogenomics Group VIB Center for Molecular Neurology Antwerp Belgium

Boston Children's Hospital Boston MA USA

Center of Medical Genetics Antwerp University Hospital University of Antwerp Edegem Belgium

Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Children's Nebraska University of Nebraska Medical Center Omaha NE USA

Department of Clinical and Molecular Genetics and Rare Disease Unit Hospital Vall d'Hebron Barcelona Spain

Department of Clinical Genetics Cook Children's Hospital Fort Worth TX USA

Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

Department of Genetics University Medical Center Utrecht Netherlands

Department of Human Genetics Children's Hospital of Philadelphia Philadelphia PA USA

Department of Human Genetics Inselspital Bern University of Bern Bern Switzerland

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Department of Paediatrics University of Melbourne Melbourne VIC Australia

Department of Pediatric Neurology University Hospital Antwerp Antwerp Belgium

Department of Pediatrics Baylor College of Medicine San Antonio TX USA

Department of Pediatrics Duke University Hospital Durham NC USA

Division of Clinical and Metabolic Genetics Hospital for Sick Children University of Toronto Toronto ON Canada

Division of Genetics and Metabolism Massachusetts General Hospital for Children Boston MA USA

Division of Medical Genetics Duke University Hospital Durham NC USA

Division of Pediatric Neurology Duke University Hospital Durham NC USA

DMG Children's Rehabilitative Services Phoenix AZ USA

GeneDx Gaithersburg MD USA

Genetics Department Mary Bridge Children's Hospital Multicare Health System Tacoma WA USA

Greenwood Genetic Center Greenwood SC USA

Harvard Medical School Boston MA USA

Institute of Human Genetics Heinrich Heine University Düsseldorf Medical Faculty Düsseldorf Germany

Institute of Human Genetics Universitätsklinikum Erlangen Friedrich Alexander Universität Erlangen Nürnberg 91054 Erlangen Germany

Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany

John T Macdonald Foundation Department of Human Genetics University of Miami Miller School of Medicine Miami FL USA

Laboratoire de Biologie Médicale Multi Sites SeqOIA Paris France

Laboratory of Medical Genetics St Sophia's Children's Hospital National and Kapodistrian University of Athens Athens Greece

McMaster University Medical Centre Hamilton ON Canada

Medical genetics department Centre Hospitalier Le Mans France

Medical Genetics Department University Hedi Chaker Hospital of Sfax Sfax Tunisia

Medicine Genetics Group Vall Hebron Research Institute Barcelona Spain

Nemours Children's Health Wilmington DE USA

NEURO Research Centre of Excellence University of Antwerp Antwerp Belgium

Orlando Health Arnold Palmer Hospital For Children Orlando FL USA

Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

School of Medicine and Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia

Service de Génétique CHU de Tours Tours France

Service de Génétique médicale Centre Labellisé Anomalies du Développement Ouest Site Poitiers France

Service de Génétique Médicale CHU d'Angers Angers France

Shodair Children's Hospital Helena MT USA

Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital Columbus OH USA

Tasmanian Clinical Genetics Service Tasmanian Health Service Hobart TAS Australia

Translational Neurosciences Faculty of Medicine and Health Science University of Antwerp Antwerp Belgium

UCL Great Ormond Street Institute of Child Health London UK

UMR1253 iBrain Inserm University of Tours Tours France

University of Calgary Calgary AB Canada

University of Utah Salt Lake City UT USA

University of Western Ontario London ON Canada

Victorian Clinical Genetics Services Murdoch Children's Research Institute Parkville VIC Australia

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Eur J Hum Genet. 2024 Aug;32(8):1032. doi: 10.1038/s41431-024-01659-y. PubMed

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