Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen, GenCC, OMIM curations. HGMD variants below

Clinical Validity Scoring Notes and points

Gene is highly constrained for LOF (pLI=1, Loeuf=0.18) and missense (z=4.77). It is located within the DiGeorge syndrome 22q11.2 deletion.

PMID: 38511226 - paper is a case report but also has good summary of prior patients, all have overlapping features of DiGeorge syndrome. However, I can’t find the primary paper for many of the citations and they aren’t listed in the references section.

• c.1A>G p.M1? absent gnomAD Variant found via proband only WES, Sanger testing later indicated it was de novo. Patient with tetralogy of Fallot, hypoplasia of corpus callosum, facial featuers, long philtrum, etc. Scoring as common / non-specific 1 POINTS (NMD- AND de novo)

• c.302+1G>C, 1 allele gnomad, previously reported in Jeanne et al(PMID: 33417013), de novo in a patient with autism spectrum, recurrent infections, DM1. Reviewed the original paper, variant found via WES. Scoring as common phenotype, 1.5 VARIANT POINTS

• Exon 2-13, OOF previously reported in Jeanne et al (PMID: 33417013) de novo in a patient with psychomotor retardation, ID, diffuse atrophy of whit ematter, microcephaly, facial features. Reviewed the original paper, this variant was found via Array. Scoring as common/non-specific 1.5 points

• Gln866Ter - previously reported with source “DDD4K.03620 (decipher patient)” in patient with vague HPO term features (abnormalities of cardiovascular, nervous system, integuement), phenotype too vague, not scoring.

• Cys315SerTer10 - previously reported Homsy et al (I am not sure which paper this is, I see it in a patient with LVO in supp database 2 in PMID: 32368696). de novo in patient with conotruncal defect. Common phenotype, and downgrading since I cant find the original paper. 0.5 POINTS

• Arg956Ter - reported by Jin et al. in a patient w/ left ventricular outflow tract obstruction, unknown if parents tested. Common phenotype, and downgrading since I cant find the original paper. 0.5 POINT

Experimental

• Jeanne et al PMID: 33417013

  • Hira knockdown in mouse hippocampal neurons which indicated it is mostly expressed during neuritogenesis and dendritogenesis stages. 0.5 point

  • Hira +/- knockout mice - minor anomalies were found, including reduced height of hipocampus at molecular layer, marginally reduced area of the corpus callosum and fornix. Only scoring this as 0.5 point since the abnormalities seemed minor and didn’t fully replicate the human phenotype..

Source:

Clinical Validity Points Total

6 points

Source:

Clinical Validity Classification

Limited

Source:

Molecular Mechanism

Suspected LOF, but GDA is limited.

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

The HIRA gene has been reported in association with a DiGeorge syndrome-like phenotype, with de novo variants reported in individuals with clinical features that overlap with DiGeorge syndrome. Reported features include congenital heart defects (tetralogy of Fallot, left ventricular outflow tract obstruction, conotruncal defect), intellectual disability, microcephaly, brain abnormalities (hypoplasia of corpus callosum, diffuse atrophy of white matter), and facial features (PMID: 38511226, 33417013, 32368696). In addition, there is some limited evidence from animal models, with a knockdown model in mouse hippocampus neurons that showed this gene is mostly expressed in neuritogenesis and dendritogenesis, and a knockout model showing some reduction of the hippocampal molecular layer, corpus callosum, and fornix (PMID: 33417013). This gene is located within the 22q11.2 deletion region and the gene is highly constrained for loss-of-function variants in gnomAD (pLI=1, Loeuf=0.18). In summary, while there is some evidence to suggest that HIRA is a candidate gene for a disorder similar to DiGeorge syndrome, the gene-disease validity is limited.

Case ID, Curator name, Date, Jira ticket link