• 0
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
H1-4 (HGNC:4718) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
H1.4 linker histone, cluster member
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
H1F4, HIST1H1E
Alias symbols
H1.4, H1e, H1s-4
%HI
49.38(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.19(Read more about gnomAD pLI score)
LOEUF
1.59(Read more about gnomAD LOEUF score)
Cytoband
6p22.2
Genomic Coordinates
GRCh37/hg19: chr6:26156557-26157343 NCBI Ensembl UCSC
GRCh38/hg38: chr6:26156329-26157115 NCBI Ensembl UCSC
MANE Select Transcript
NM_005321.3 ENST00000304218.6 (Read more about MANE Select)
Function
Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation (By similarity). {ECO:0000250}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-14986
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
No Evidence for Haploinsufficiency (0)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
07/27/2022

Haploinsufficiency (HI) Score Details

HI Score:
0
HI Evidence Strength:
No Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 28475857
    Tatton-Brown et al. 2017: Exome sequencing 710 individuals with overgrowth and intellectual disability. Within this cohort, 323 individuals had both parents available. Five unrelated probands were identified with heterozygous HIST1H1E protein truncating variants. All the five patients had full cheeks and high hairline. In four probands the variants were de novo, parental samples were not available for the fifth child. The mutations identified in these five individuals represent three different mutations: 2 unrelated patients carried de novo c.430dupG; 2 unrelated patients carried c.441dupC (one is de novo, the other one is unknown); and a 1.9-year-old girl with a diagnosis of Rahman syndrome carried de novo c.436_458del23. All those three variants were identified cluster significantly (p= 2.0 3x10-9) to a 12-bp region in the carboxyterminal domain (CTD) that is involved in chromatin binding and protein-protein interactions. None of the mutations are present in the ExAC dataset, nor in 11,677 exomes analyzed in-house with similar pipelines. Of note, Takenouchi et al. 2018 commented on this study and mentioned that the growth pattern of these five patients appeared complex: 4/5 patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Therefore, the overgrowth phenotype is controversial and main phenotype associated with HIST1H1E remains intellectual disability. *No cellular or molecular assays were performed to suggest molecular mechanism.
  • PUBMED: 29704315
    Duffney et al., 2018: A de novo deleterious mutation of HIST1H1E (c.435dupC; p.Thr146Hisfs*50) was identified by WES in a 10-year-old boy with autism, intellectual disability, and potential overgrowth [his weight is 54.5kg (98th percentile), height is 144.8cm (70th percentile), and head circumference is 53cm (45th percentile)]. He has minor dysmorphic facial features, including downward-slanting palpebral fissures, hypertelorism, light eyebrows, micro and retrognathia, and wide philtrum. The authors note that the "c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression by western blot, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain." This variant was not found in ExAc, dbSNP, 1000G, or ESP.
  • PUBMED: 29383847
    Takenouchi et al. 2018: A female patient with intellectual disability (ID) and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup/chr6 (GRCh37): g.26157051dup, which predicted a premature termination of the protein, p. Ala145Glyfs*51. This duplication was located within the 12-bp, (chr6 (GRCh37):g.26157048-g.26157059), region in the carboxyl terminal domain of HIST1H1E gene. This author also summarized the growth pattern of seven patients with HIST1H1E mutations and concluded that skeletal overgrowth is not an essential feature of HIST1H1E-related disorder. This HIST1H1E-related disorder is suggested to be referred to as Rahman syndrome. *No cellular or molecular assays were performed to suggest molecular mechanism.
  • PUBMED: 31447100
    Flex et al 2019 strongly suggested a dominant negative or neomorphic effect as the mechanism of disease. Haploinsufficiency was considered unlikely due to several evidences: 1. Endogenous HIST1H1E mRNA levels from two unrelated affected subjects were comparable to those of controls. 2. Molecular and cellular assays performed by the authors suggest truncated protein with increased stability, proper nuclear localization and stable binding to chromatin, which are not compatible with haploinsufficiency as disease mechanism. 3. The authors mention two articles using animal models (PMID: 7604008; 11689686) as inactivation of any of H1 histones does not significantly perturb murine development, which is compromised only when a concomitant inactivation of multiple subtypes occurs suggesting high functional redundancy and no HIST1H1E's ortholog dosage sensitivity. 4. Truncated variants observed in gnomAD affect protein regions that do not overlap the mutational hotspot identified by the authors but are much more proximal to the N-terminus or to the C-terminus. The authors also mention H1 histones C-terminal contains several serine and threonine residues which are lost in disease-associated HIST1H1E mutants. C-terminal region modulates chromatin compaction and its full phosphorylation is required for maximal condensation during mitosis. As a consequence of such mutations, the authors observed significantly higher frequency of aneuploidy in cellular assays. They concluded their data do not support haploinsufficiency as molecular mechanism implicated in pathogenesis but a "dominantly acting effect causing a profound perturbation of multiple cellular processes directly and indirectly controlled by chromatin remodeling."
HI Evidence Comments:
According to GeneReviews (NBK564966), at this time, whole-gene deletions or duplications have not been identified as a cause of this disorder. "To date all individuals reported with the recognizable pattern of findings characteristic of HIST1H1E syndrome have had frameshift variants in the carboxy terminal domain. No affected individuals with other sequence variants or gene dosage abnormalities have been reported." To date, all patients with HIST1H1E syndrome have truncated de novo mutations that are short out-of-frame indels resulting in almost identical shorter proteins that contained a shared divergent C-terminal tail. HIST1H1E is a single exon gene and evidences from patients' samples and cellular assays suggest these mutants escape nonsense-mediated mRNA decay and result in stable truncated proteins (PMID: 31447100). Note: HIST1H1E is a previous symbol for H1-4; much of the available literature refers to this gene using this older nomenclature.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000006.11) (NC_000006.12)