Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: H4C9
Cytogenetic location: 6p22.1 Genomic coordinates (GRCh38): 6:27,139,282-27,139,678 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.1 | Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 4 | 619951 | Autosomal dominant | 3 |
For background information on histones, histone gene clusters, and the H4 histone family, see HIST1H4A (602822).
By cloning the junctional area of a recurring translocation, t(3;6)(q27;p21), in B cell-type non-Hodgkin lymphoma, Akasaka et al. (1997) identified a gene encoding a member of the H4 class of histones. Albig and Doenecke (1997) designated this gene H4/m.
By genomic sequence analysis, Marzluff et al. (2002) identified the mouse and human HIST1H4I genes. All mouse and human H4 genes, including HIST1H4I, encode the same protein.
By FISH, Akasaka et al. (1997) mapped the H4/m gene to chromosome 6p21.3, within the cluster of histone genes in this region.
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 HIST1H4I.
See HIST1H4A (602822) for functional information on H4 histones.
In 2 cases of patients carrying the t(3;6)(q27;p21) translocation, Akasaka et al. (1997) found that the H4/m gene was substituted for the 5-prime regulatory elements of BCL6 (109565) and fused with coding exons 3-9 of BCL6 in the same transcriptional orientation. Since H4 gene expression is tightly coupled to DNA replication, these authors suggested that the translocation causes inappropriate expression of BCL6 during the cell cycle, leading to the development of non-Hodgkin lymphoma.
In 3 unrelated patients (P26-P28) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4; 619951), Tessadori et al. (2022) identified de novo heterozygous missense mutations in the core globular domain of the H4C9 gene (R41L; 602833.0001 and H76R; 602833.0002). The patients were ascertained through international collaboration after the mutations were identified by exome sequencing. Neither was present in the gnomAD database. Expression of the mutations into zebrafish embryos induced severe developmental defects, suggesting that they are pathogenic. The authors postulated a dominant effect. All patients had 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 10.5-year-old girl (P26) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4; 619951), Tessadori et al. (2022) identified a de novo heterozygous c.122G-T transversion (c.122G-T, NM_003495.2) in the H4C9 gene, resulting in an arg41-to-leu (R41L) 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 learning difficulties, social communication problems, poor growth with microcephaly (-4.12 SD), visual and hearing deficits, and dysmorphic facial features. The authors also referred to this mutation as ARG40LEU (R40L), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
In 2 unrelated patients (P27 and P28) with Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4; 619951), Tessadori et al. (2022) identified a de novo heterozygous c.227A-G transition (c.227A-G, NM_003495.2) in the H4C9 gene, resulting in a his76-to-arg (H76R) 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 into zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. The patients had poor overall growth, global developmental delay with intellectual disability, dysmorphic features, and skeletal anomalies. P28 died at 29 years of age, presumably from myelodysplasia and leukemia. The authors also referred to this mutation as HIS75ARG (H75R), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.
Akasaka, T., Miura, I., Takahashi, N., Akasaka, H., Yonetani, N., Ohno, H., Fukuhara, S., Okuma, M. A recurring translocation, t(3;6)(q27;p21), in non-Hodgkin's lymphoma results in replacement of the 5-prime regulatory region of BCL6 with a novel H4 histone gene. Cancer Res. 57: 7-12, 1997. [PubMed: 8988030]
Albig, W., Doenecke, D. The human histone gene cluster at the D6S105 locus. Hum. Genet. 101: 284-294, 1997. [PubMed: 9439656] [Full Text: https://doi.org/10.1007/s004390050630]
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]