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Intellectual disability

Gene: HIRA

Amber List (moderate evidence)

HIRA (histone cell cycle regulator)
EnsemblGeneIds (GRCh38): ENSG00000100084
EnsemblGeneIds (GRCh37): ENSG00000100084
OMIM: 600237, Gene2Phenotype
HIRA is in 1 panel

2 reviews

Arina Puzriakova (Genomics England Curator)

I don't know

Comment on list classification: New gene added by Zornitza Stark. At least 4 unrelated individuals with heterozygous variants in this gene - however, only 1 presented moderate ID (2 had ASD rather than ID, while the phenotype is unclear for the fourth individual). HIRA is a good candidate for neurodevelopmental impairment, supported by an animal model, but additional cases are required to ascertain the relevance of ID.

Therefore, at present there is only enough evidence to rate Amber awaiting further cases/clinical evidence (added 'watchlist' tag)
Created: 9 Feb 2021, 11:10 a.m. | Last Modified: 9 Feb 2021, 11:10 a.m.
Panel Version: 3.766
Currently this gene is not associated with any phenotype in OMIM, but has a 'possible' disease confidence for 'HIRA-related neurodevelopmental disorder' in Gene2Phenotype.

Jeanne et al. 2021 (PMID: 33417013) report on 2 unrelated individuals with de novo heterozygous truncating variants in the HIRA gene. Both presented a neurodevelopmental disorder which was characterised by hypotonia, psychomotor retardation, moderate ID, mild microcephaly, motor stereotypies, and white matter atrophy in one patient; while the other individual presented only behavioural problems mainly confined to symptoms of ASD.

Authors also identified two additional independently reported cases with different de novo heterozygous HIRA variants (PMIDs: 28135719 and 25363760). Clinical details were not provided in either case; however, one was recruited as part of the DDD study, while the other was investigated as part of a large autism spectrum disorder cohort.

Heterozygous Hira knock-out in mice resulted in mild neuroanatomical defects and impaired neurogenesis in primary neurons.
Created: 9 Feb 2021, 10:57 a.m. | Last Modified: 9 Feb 2021, 10:57 a.m.
Panel Version: 3.765

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Two unrelated patients with different de novo loss of function variants identified in PMID 33417013:

Individual 1: intragenic deletion, phenotype included psychomotor retardation, ID, growth retardation, microcephaly, and facial features reminiscent of 22q deletion syndrome.
Individual 2: canonical splice variant, phenotype mostly confined to ASD

Another two de novo variants were identified in the literature by the authors of that paper, one stop-gain (DDD study, PMID 28135719) and one missense (large autism cohort, PMID 25363760).

PMID 33417013 also showed that HIRA knockdown in mice results in neurodevelopmental abnormalities.

Rated Green due to 4 unrelated individuals (albeit 2 in large cohort studies) and a mouse model. NB: HIRA is within the common 22q deletion region.
Sources: Literature
Created: 1 Feb 2021, 10:54 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Neurodevelopmental disorder
Tags
watchlist
OMIM
600237
Clinvar variants
Variants in HIRA
Penetrance
None
Publications
Panels with this gene

History Filter Activity

9 Feb 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: hira has been classified as Amber List (Moderate Evidence).

9 Feb 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist tag was added to gene: HIRA.

1 Feb 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: HIRA was added gene: HIRA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HIRA were set to 33417013; 28135719; 25363760 Phenotypes for gene: HIRA were set to Neurodevelopmental disorder Review for gene: HIRA was set to GREEN gene: HIRA was marked as current diagnostic