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

• Published in: Journal of medical genetics Vol. 59; no. 10; pp. 1027 - 1034
• Main Authors: Kieninger, Sinja, Xiao, Ting, Weisschuh, Nicole, Kohl, Susanne, Rüther, Klaus, Kroisel, Peter Michael, Brockmann, Tobias, Knappe, Steffi, Kellner, Ulrich, Lagrèze, Wolf, Mazzola, Pascale, Haack, Tobias B, Wissinger, Bernd, Tonagel, Felix
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.10.2022; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Alzheimer's disease; Atrophy; Cloning; DNA, Mitochondrial - genetics; eye diseases; Females; Founder effect; Gender; Gene deletion; Genomes; HSP40 Heat-Shock Proteins - genetics; human genetics; Humans; Males; Maternal inheritance; Mitochondria - genetics; Mitochondrial DNA; Mutation; Optic atrophy; Optic Atrophy, Hereditary, Leber - diagnosis; Optic Atrophy, Hereditary, Leber - epidemiology; Optic Atrophy, Hereditary, Leber - genetics; Optic neuropathy; Patients; Vision Science; Germany; human genetics; eye diseases
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2021-108235

BackgroundLeber’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 resultsIn 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.ConclusionThis study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.