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

Publication ,  Journal Article
Layo-Carris, DE; Lubin, EE; Sangree, AK; Clark, KJ; Durham, EL; Gonzalez, EM; Smith, S; Angireddy, R; Wang, XM; Weiss, E; Toutain, A; Ziats, C ...
Published in: Eur J Hum Genet
August 2024

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 Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals.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

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Published In

Eur J Hum Genet

DOI

EISSN

1476-5438

Publication Date

August 2024

Volume

32

Issue

8

Start / End Page

928 / 937

Location

England

Related Subject Headings

  • Phenotype
  • Neurodevelopmental Disorders
  • Neurodegenerative Diseases
  • Male
  • Intellectual Disability
  • Humans
  • Histones
  • Genetics & Heredity
  • Female
  • Child, Preschool
 

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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. Eur J Hum Genet, 32(8), 928–937. https://doi.org/10.1038/s41431-024-01610-1
Layo-Carris, Dana E., Emily E. Lubin, Annabel K. Sangree, Kelly J. Clark, Emily L. Durham, Elizabeth M. Gonzalez, Sarina Smith, et al. “Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.Eur J Hum Genet 32, no. 8 (August 2024): 928–37. https://doi.org/10.1038/s41431-024-01610-1.
Layo-Carris DE, Lubin EE, Sangree AK, Clark KJ, Durham EL, Gonzalez EM, et al. Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals. Eur J Hum Genet. 2024 Aug;32(8):928–37.
Layo-Carris, Dana E., et al. “Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.Eur J Hum Genet, vol. 32, no. 8, Aug. 2024, pp. 928–37. Pubmed, doi:10.1038/s41431-024-01610-1.
Layo-Carris DE, Lubin EE, Sangree AK, Clark KJ, Durham EL, Gonzalez EM, Smith S, Angireddy R, Wang XM, Weiss E, Toutain A, 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 MJM, 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 M-L, Gueguen P, Derive N, Colin E, Battault C, Au B, Delatycki M, Wallis M, Gallacher L, Majdoub F, Smal N, Weckhuysen S, Schoonjans A-S, 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 EJK, Bryant LM. Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals. Eur J Hum Genet. 2024 Aug;32(8):928–937.

Published In

Eur J Hum Genet

DOI

EISSN

1476-5438

Publication Date

August 2024

Volume

32

Issue

8

Start / End Page

928 / 937

Location

England

Related Subject Headings

  • Phenotype
  • Neurodevelopmental Disorders
  • Neurodegenerative Diseases
  • Male
  • Intellectual Disability
  • Humans
  • Histones
  • Genetics & Heredity
  • Female
  • Child, Preschool