Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals
Copyright policy )Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals
AbstractBryant-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 Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals.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.
- University of Utah United States
- Panagiotis & Aglaia Kyriakou Children's Hospital Greece
- University of Calgary Canada
- University of Erlangen-Nuremberg Germany
- University of Bern Switzerland
Male, PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico, Intellectual disability, Gene, Histones, Genetic heterogeneity, FENÓMENOS Y PROCESOS::fenómenos genéticos::fenotipo, PHENOMENA AND PROCESSES::Genetic Phenomena::Phenotype, Genetics(clinical), Missense mutation, Child, Life Sciences, Neurodegenerative Diseases, Genomic Rearrangements and Copy Number Variations, Fenotip, Chemistry, Phenotype, Child, Preschool, Molecular Basis of Rett Syndrome and Related Disorders, Female, Epigenetics, Trastorns del desenvolupament - Aspectes genètics, Adult, 570, Adolescent, 610, 610 Medicine & health, Hypotonia, Adolescent [MeSH] ; Female [MeSH] ; Adult [MeSH] ; Histones/genetics [MeSH] ; Humans [MeSH] ; Neurodevelopmental Disorders/pathology [MeSH] ; Intellectual Disability/genetics [MeSH] ; /631/208/1516 ; Neurodegenerative Diseases/pathology [MeSH] ; Neurodevelopmental Disorders/genetics [MeSH] ; Neurodegenerative Diseases/genetics [MeSH] ; Intellectual Disability/pathology [MeSH] ; /631/208/366 ; Article ; Male [MeSH] ; Phenotype [MeSH] ; Child [MeSH] ; article ; Child, Preschool [MeSH], Article, Neurodevelopmental disorder, Intellectual Disability, Biochemistry, Genetics and Molecular Biology, Journal Article, Genetics, DISEASES::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Neurologic Manifestations::Neurobehavioral Manifestations::Intellectual Disability, ENFERMEDADES::afecciones patológicas, signos y síntomas::signos y síntomas::manifestaciones neurológicas::manifestaciones neuroconductuales::discapacidad intelectual, Humans, Discapacitat intel·lectual, Biology, Brain Development, Standards and Guidelines for Genetic Variant Interpretation, Neurodevelopmental Disorders, FOS: Biological sciences, Human medicine, PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders
Male, PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico, Intellectual disability, Gene, Histones, Genetic heterogeneity, FENÓMENOS Y PROCESOS::fenómenos genéticos::fenotipo, PHENOMENA AND PROCESSES::Genetic Phenomena::Phenotype, Genetics(clinical), Missense mutation, Child, Life Sciences, Neurodegenerative Diseases, Genomic Rearrangements and Copy Number Variations, Fenotip, Chemistry, Phenotype, Child, Preschool, Molecular Basis of Rett Syndrome and Related Disorders, Female, Epigenetics, Trastorns del desenvolupament - Aspectes genètics, Adult, 570, Adolescent, 610, 610 Medicine & health, Hypotonia, Adolescent [MeSH] ; Female [MeSH] ; Adult [MeSH] ; Histones/genetics [MeSH] ; Humans [MeSH] ; Neurodevelopmental Disorders/pathology [MeSH] ; Intellectual Disability/genetics [MeSH] ; /631/208/1516 ; Neurodegenerative Diseases/pathology [MeSH] ; Neurodevelopmental Disorders/genetics [MeSH] ; Neurodegenerative Diseases/genetics [MeSH] ; Intellectual Disability/pathology [MeSH] ; /631/208/366 ; Article ; Male [MeSH] ; Phenotype [MeSH] ; Child [MeSH] ; article ; Child, Preschool [MeSH], Article, Neurodevelopmental disorder, Intellectual Disability, Biochemistry, Genetics and Molecular Biology, Journal Article, Genetics, DISEASES::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Neurologic Manifestations::Neurobehavioral Manifestations::Intellectual Disability, ENFERMEDADES::afecciones patológicas, signos y síntomas::signos y síntomas::manifestaciones neurológicas::manifestaciones neuroconductuales::discapacidad intelectual, Humans, Discapacitat intel·lectual, Biology, Brain Development, Standards and Guidelines for Genetic Variant Interpretation, Neurodevelopmental Disorders, FOS: Biological sciences, Human medicine, PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders
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