Intellectual disability - microarray and sequencing
Gene: HIST1H4J
Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.
There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.
Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).
Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).
Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).
Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).
Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).
Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.
Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.
Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.
Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).
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Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].
Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).
Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).
RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).
Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.
Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.
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In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).
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Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).
All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).
The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.
Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.
Previous work-up or presence of additional variants are not discussed.
At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.
There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).
All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).
Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).
For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.
H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.
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[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]Created: 18 Mar 2022, 3:50 p.m. | Last Modified: 18 Mar 2022, 3:50 p.m.
Panel Version: 3.1520
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Comment on list classification: Amber rating as additional cases are required to validate pathogenicity, but added to watchlist.Created: 24 Jul 2020, 1:07 p.m. | Last Modified: 24 Jul 2020, 1:07 p.m.
Panel Version: 3.201
Added new-gene-name tag, new approved HGNC gene symbol is H4C11.
This is a possible gene for intellectual disability with facial dysmorphism in G2P.
Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.Created: 24 Jul 2020, 1:04 p.m. | Last Modified: 24 Jul 2020, 1:08 p.m.
Panel Version: 3.201
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Microcephaly; Intellectual disability; Dysmorphic facial features; Growth delay
Publications
Single case report but with functional evidence in zebrafish and phenotypic similarity to HIST1H4C phenotype
Sources: LiteratureCreated: 3 Jun 2020, 11:02 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
microcephaly; intellectual disability; dysmorphic features
Publications
Tag watchlist tag was added to gene: HIST1H4J.
Phenotypes for gene: HIST1H4J were changed from microcephaly; intellectual disability; dysmorphic features to ?Tessadori-van Haaften neurodevelopmental syndrome 2 , OMIM:619759
Publications for gene: HIST1H4J were set to 31804630; 35202563
Publications for gene: HIST1H4J were set to 31804630
Gene: hist1h4j has been classified as Amber List (Moderate Evidence).
gene: HIST1H4J was added gene: HIST1H4J was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HIST1H4J were set to 31804630 Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features Review for gene: HIST1H4J was set to AMBER