Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.
Bryant-Li-Bhoj syndrome can look completely different in two people with the same gene variant, so treat the child, not the label.
01Research in Context
What this study did
Doctors looked at 96 people with Bryant-Li-Bhoj syndrome. They wrote down each person’s delays, behavior, and medical issues. The goal was to see how the same gene change can look very different.
What they found
Even brothers with the exact H3.3 variant can act and learn in very different ways. Where the DNA change sits, not the child’s sex, seems to shape how serious things get.
How this fits with other research
Green Snyder et al. (2016) first showed that 16p11.2 duplications also give a mixed picture—only one in five kids get an ASD label. DAdams et al. (2024) now extend that idea: rare gene changes almost always create a wide, unpredictable range.
de Leeuw et al. (2024) used the same 2024 case-series style on 16p11.2 kids and found clear social-communication problems. BLBS is different; social issues appear in some but not all, so the two studies look opposite yet simply map two syndromes.
McGhee et al. (2025) linked one PTPN11 gene spot to stronger ASD traits in Noonan syndrome. BLBS shows no tidy link, reminding us that one gene can give clean rules in one syndrome and pure chaos in another.
Why it matters
When you meet a child with BLBS, throw away the “classic” picture. Assess the individual in front of you, not the gene. Plan for big swings—one child may need an AAC device while a sibling needs only mild classroom help. Share this reality with parents so they expect variability, not a fixed roadmap.
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02At a glance
03Original 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 Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals.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.
, 2024 · doi:10.1038/s41431-024-01610-1