DNAJC30 disease-causing gene variants in a large Central European cohort of patients with inherited optic atrophy

Abstract

Purpose : Leber’s hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inherited disease. However, recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30. We performed a retrospective screening of DNAJC30 in a large series of genetically unsolved patients clinically diagnosed with LHON patients or other forms of inherited optic atrophy (OA). We compiled and compared the prevalence, patients’ demography and clinical findings with those linked to mtDNA variants.

Methods : 1202 patients (1197 index patients and 5 affected family members, male: female ratio 1.8:1) were retrospectively selected for DNAJC30 screening, including 800 patients with a clinical diagnosis of LHON and 402 patients with OA. Genomic DNA samples of patients were used for screening of the coding sequence of DNAJC30 gene and its flanking untranslated regions by PCR amplification and subsequent Sanger sequencing. Pathogenicity of variants was assessed by in silico software prediction, allele frequency, and segregation analysis. Microsatellite marker analysis was performed to analyze the founder effect for the variant c.152A>G;p.(Tyr51Cys). Clinical examinations include visual acuity measurement, slit lamp examination, perimetry, indirect ophthalmoscopy, optical coherence tomography and color vision (Ishihara plates and Farnsworth-Munsell Dichotomous D-15 test).

Results : We identified likely pathogenic variants in 2.9% (35/1202) patients. The missense variant c.152A>G;p.(Tyr51Cys) accounted for 90% of disease-associated alleles in our cohort. Marker analysis provided strong evidence for a founder effect and a common origin of this mutation. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared to LHON associated with disease-causing variants in the mitochondrial DNA (mtLHON).

Conclusions : This study expands previous findings on arLHON and emphasizes the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.