Perrault syndrome is genetically heterogeneous. Biallelic variants in HARS2 have been identified in a small proportion of all cases reported with Perrault syndrome.
The majority of pathogenic variants reported to date have been missense. It is likely that these are hypomorphic, resulting in reduced HARS2 enzyme activity. Loss of function (nonsense and frameshift) variants have only been described in trans with a missense variant. Biallelic null variants are unlikely to be viable.
One variant c.1439G>A p.(Arg480His) has been reported in multiple unrelated individuals.
Diagnostic testing is available as a single gene, as part of panels associated with hearing loss or ovarian insufficiency or through exome or genome sequencing analysis.
Aminoacylation assays to demonstrate the effect of HARS2 variants on enzyme activity are not routinely available.
HARS2