HARS2 and Perrault syndrome

Perrault syndrome is a rare autosomal recessive disorder characterized primarily by sensorineural hearing impairment and ovarian dysfunction. Multiple independent studies have identified pathogenic variants in the mitochondrial histidyl-tRNA synthetase gene (HARS2), establishing its critical role in the disease mechanism (PMID:33228777).

In one study, a Chinese family with two affected male siblings was found to harbor the variant c.349G>A (p.Asp117Asn) in HARS2, supporting its causative role in sensorineural hearing loss, a hallmark of Perrault syndrome (PMID:33228777). Additional reports, including a nonconsanguineous family with five affected siblings, further strengthen the association by documenting consistent segregation of biallelic HARS2 variants with the disease phenotype (PMID:21464306).

Genetic evidence across these cases includes a range of variant classes such as missense, frameshift, and nonsense mutations that disrupt critical conserved residues, demonstrating a dose-dependent pathogenicity. The recurrent detection of variants like c.349G>A (p.Asp117Asn) in unrelated families underscores the robustness of the genetic association and the autosomal recessive inheritance pattern.

Complementary functional studies have provided additional support for the pathogenic mechanism. In vitro assays and model organism experiments, including yeast complementation and cybrid studies, have shown that mutant HARS2 exhibits reduced aminoacylation activity and impaired protein function, which is consistent with the mitochondrial dysfunction observed in affected patients (PMID:31819004, PMID:23541342).

Moreover, segregation analyses across multiple families have confirmed that the HARS2 variants co‐segregate with the phenotype, consolidating the genetic and functional data into a coherent narrative of disease causality. Although some reports suggest phenotypic variability, the overall integration of the evidence supports a strong association between HARS2 variants and Perrault syndrome.

Together, these data provide compelling evidence that pathogenic variants in HARS2 are a strong diagnostic marker for Perrault syndrome, facilitating effective genetic counselling and targeted clinical management for affected individuals.

Key Take‑home: The cumulative genetic and functional evidence robustly establishes HARS2 as a definitive diagnostic marker for Perrault syndrome, enabling precise evaluation and personalised management of patients.

References

• Hereditas • 2020 • Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss PMID:33228777
• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome PMID:21464306
• The Journal of Biological Chemistry • 2020 • Overexpression of mitochondrial histidyl-tRNA synthetase restores mitochondrial dysfunction caused by a deafness-associated tRNAHis mutation PMID:31819004
• American Journal of Human Genetics • 2013 • Mutations in LARS2 lead to premature ovarian failure and hearing loss in Perrault syndrome PMID:23541342

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