Alternative titles; symbols
HGNC Approved Gene Symbol: H4C5
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38): 6:26,204,610-26,205,021 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.2 | Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 3 | 619950 | Autosomal dominant | 3 |
For background information on histones, histone gene clusters, and the H4 histone family, see HIST1H4A (602822).
By genomic sequence analysis, Marzluff et al. (2002) identified the human HIST1H4E gene. All H4 genes, including HIST1H4E, encode the same protein.
By analysis of a YAC contig from chromosome 6p21.3, Albig et al. (1997) characterized a cluster of 35 histone genes, including H4/j.
By genomic sequence analysis, Marzluff et al. (2002) determined that the histone gene cluster on chromosome 6p22-p21, which they called histone gene cluster-1 (HIST1), contains 55 histone genes, including HIST1H4E.
See HIST1H4A (602822) for functional information on H4 histones.
In 17 unrelated patients with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified de novo heterozygous missense mutations in the H4C5 gene (see, e.g., 602830.0001-602830.0005). The patients were ascertained through international collaboration after the mutations were identified by exome sequencing. Some of the variants (e.g., R46C; 602830.0004) were recurrent; none were present in the gnomAD database. The mutations occurred at conserved residues and tended to cluster in the core globular domain or the C-tail domain. Expression of some of the mutations in zebrafish embryos induced developmental defects, suggesting that they are pathogenic. The authors postulated a dominant effect. Of note, 4 patients (P12-P15) carried the same R41C missense variant, which was not present in gnomAD but did not induce significant developmental defects when expressed in zebrafish embryos. All patients had global developmental delay, but the severity and manifestations were highly variable, even in those with the same genotype. Tessadori et al. (2022) stated that there were inherent limitations in the zebrafish assays.
In a 11-month-old girl (P8) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.95A-C transversion (c.95A-C, NM_003545.3) in the H4C5 gene, resulting in a lys32-to-thr (K32T) substitution at a conserved residue in the core globular domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. She had global developmental delay with poor growth. The authors also referred to this mutation as LYS31THR (K31T), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
In a 5-year-old boy (P9) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.98C-G transversion (c.98C-G, NM_003545.3) in the H4C5 gene, resulting in a pro33-to-arg (P33R) substitution at a conserved residue in the core globular domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. He had global developmental delay with inability to walk or speak, spasticity, and seizures. The authors also referred to this mutation as PRO32ARG (P32R), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
In a 12.5-year-old female (P10) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.106C-T transition (c.106C-T, NM_003545.3) in the H4C5 gene, resulting in an arg36-to-trp (R36W) substitution at a conserved residue in the core globular domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. The patient had developmental delay and autism. The authors also referred to this mutation as ARG35TRP (R35W), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
In 7 unrelated patients (P16-P22) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.136C-T transition (c.136C-T, NM_003545.3) in the H4C5 gene, resulting in an arg46-to-cys (R46C) substitution at a conserved residue in the core globular domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced mild developmental defects that just reached significance (p less that 0.05), suggesting that it may be pathogenic. The authors postulated a dominant effect. The patients had poor overall growth and global developmental delay, but there was phenotypic heterogeneity. The authors also referred to this mutation as ARG45CYS (R45C), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
In 2 unrelated patients (P23 and P24) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3; 619950), Tessadori et al. (2022) identified a de novo heterozygous c.295T-C transition (c.295T-C, NM_003545.3) in the H4C5 gene, resulting in an tyr99-to-his (Y99H) substitution at a conserved residue in the C-tail domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it may be pathogenic. The authors postulated a dominant effect. The patients had poor overall growth and global developmental delay, but there was phenotypic heterogeneity. The authors also referred to this mutation as TYR98HIS (Y98H), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
Albig, W., Kioschis, P., Poustka, A., Meergans, K., Doenecke, D. Human histone gene organization: nonregular arrangement within a large cluster. Genomics 40: 314-322, 1997. [PubMed: 9119399] [Full Text: https://doi.org/10.1006/geno.1996.4592]
Marzluff, W. F., Gongidi, P., Woods, K. R., Jin, J., Maltais, L. J. The human and mouse replication-dependent histone genes. Genomics 80: 487-498, 2002. [PubMed: 12408966]
Tessadori, F., Duran, K., Knapp, K., Fellner, M., Deciphering Developmental Disorders Study, Smithson, S., Beleza Meireles, A., Elting, M. W., Waisfisz, Q., O'Donnell-Luria, A., Nowak, C., Douglas, J., and 54 others. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome. Am. J. Hum. Genet. 109: 750-758, 2022. [PubMed: 35202563] [Full Text: https://doi.org/10.1016/j.ajhg.2022.02.003]