HIRA – Neurodevelopmental Disorder

Heterozygous loss-of-function variants in HIRA have been identified in two unrelated patients with neurodevelopmental disorder, each harboring a de novo truncating allele and demonstrating impaired dendritic growth in vitro and subtle neuroanatomical defects in Hira+/– mice, supporting haploinsufficiency as the pathogenic mechanism ([PMID:33417013]). Population screening of 200 632 UK Biobank exomes revealed four additional carriers of predicted HIRA frameshift or stop variants—only one with depression—indicating variable penetrance of neuropsychiatric features ([PMID:34074949]).

Functional studies demonstrate that a twofold reduction of HIRA expression in primary mouse hippocampal neurons leads to reduced dendritic outgrowth and branching, while Hira+/– mice exhibit reduced hippocampal, fornix, and corpus callosum volumes, concordant with impaired neurogenesis and connectivity. Together, these data meet ClinGen criteria for a Limited gene–disease association, with Moderate functional support but without extensive segregation or case numbers beyond two probands. Additional evidence from broader cohorts suggests incomplete penetrance and warrants further study.

Key Take-home: HIRA haploinsufficiency is a plausible but still limited contributor to neurodevelopmental disorder, with variable expressivity that should inform genetic counseling and surveillance for psychiatric manifestations.

References

• Psychiatric genetics • 2021 • Haploinsufficiency of the HIRA gene may not always produce severe neurodevelopmental consequences. PMID:34074949
• Human genetics • 2021 • Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth. PMID:33417013

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