DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy

Abstract

Background: Leber's hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30.

Methods and results: In this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. 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 with LHON associated with disease-causing variants in the mitochondrial DNA.

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

Keywords: eye diseases; human genetics.

Figure 1

Scheme of the DNAJC30 protein domains and location of the variants. Variant p.(Tyr51Cys), p.(His77del), p.(Pro78Ser) and p.(Leu101Gln) are located in the J domain. The variant p.(Glu204*) is located upstream of the transmembrane domain. Novel variants detected in our study are indicated in red.

Figure 2

Representative electropherograms of detected pathogenic sequence variants. The upper sequence digits represent the wild-type sequence. The mutant sequence corresponds to the lower sequence digits. The red box highlights the position of the variant. (A, B) Patient LHON 96, LHON 573 and LHON 1149 carry the compound heterozygous variants c.152A>G and c.610G>T. (C) Patient OAK 559 (19776) and his brother OAK 559 (31530) carry the 3 bp deletion c.230_232del in homozygous state. (D) Thirty patients carry the missense variant c.152A>G in homozygous state. LHON, Leber’s hereditary optic neuropathy.

Figure 3

The c.152A>G variant is a founder variant. Allele spectrum (x-axis=allele size, y-axis=relative frequency) of marker D7S809 on chromosomes bearing DNAJC30: c.152A>G variant (black bars) in comparison to non-mutant chromosomes from controls (white bars). The 287 bp allele is strongly over-represented on disease-linked chromosomes (85% vs 12.5% on control chromosomes) indicating a founder effect.

Figure 4

Exemplary clinical findings of DNAJC30-associated arLHON-affected patients. (A) Cecocentral visual field defect in patient LHON 1088. (B) Papillary hyperaemia (white arrows) and peripapillary microangiopathy (black arrows) shortly after onset of the disease in patient LHON 1089. (C) Temporally accentuated papillary atrophy occurring in the further course of the disease (in patient OAK 767). (D) Optical coherence tomography scan of the RNFL showing a temporal decrease of thickness in OAK 767. arLHON, autosomal recessive inherited form of LHON; LHON, Leber’s hereditary optic neuropathy.