PUBLICATION
A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder
- Authors
- Tessadori, F., Rehman, A.U., Giltay, J.C., Xia, F., Streff, H., Duran, K., Bakkers, J., Lalani, S.R., van Haaften, G.
- ID
- ZDB-PUB-191206-26
- Date
- 2019
- Source
- European journal of human genetics : EJHG 28(5): 674-678 (Journal)
- Registered Authors
- Bakkers, Jeroen, Duran, Andrea
- Keywords
- none
- MeSH Terms
-
- Adolescent
- Animals
- Craniofacial Abnormalities/genetics*
- Craniofacial Abnormalities/pathology
- Developmental Disabilities/genetics*
- Developmental Disabilities/pathology
- Disease Models, Animal*
- Histones/genetics*
- Histones/metabolism
- Humans
- Intellectual Disability/genetics*
- Intellectual Disability/pathology
- Male
- Mutation, Missense
- Syndrome
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 31804630 Full text @ Eur. J. Hum. Genet.
Citation
Tessadori, F., Rehman, A.U., Giltay, J.C., Xia, F., Streff, H., Duran, K., Bakkers, J., Lalani, S.R., van Haaften, G. (2019) A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder. European journal of human genetics : EJHG. 28(5):674-678.
Abstract
We report here a de novo missense variant in HIST1H4J resulting in a complex syndrome combining growth delay, microcephaly and intellectual disability. Trio whole exome sequencing (WES) revealed that the proband was heterozygous for a de novo c.274 A > G p.(K91E) variant in HIST1H4J, a gene not yet associated with human disease. The patient presented with profound intellectual disability, microcephaly, and dysmorphic facial features. Functional consequences of the identified de novo missense variant were evaluated in zebrafish embryos, where they affected general development, especially resulting in defective head organs and reduced body axis length. Our results show that the monoallelic p.K91E substitution on HIST1H4J underlies a human syndrome that is genetically and phenotypically akin to the HIST1H4C-associated neurodevelopmental disorder resulting from p.K91A and p.K91Q substitions in HIST1H4C. The highly overlapping patient phenotypes highlight functional similarities between HIST1H4J and HIST1H4C perturbations, establishing the singular importance of K91 across histone H4 genes for vertebrate development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping