Autosomal recessive Leber's hereditary optic neuropathy caused by a homozygous variant in DNAJC30 gene.

Recently, Stenton et al. (2021) described a new, autosomal recessive inheritance pattern of Leber's hereditary optic neuropathy (LHON) caused by missense variants in the DNAJC30 gene. The DNAJC30 c.152A > G, p.(Tyr51Cys) variant was by far the most common variant reported in patients originating from Eastern Europe, therefore, it is believed to be a founder variant in these populations. We report the first two cases of DNAJC30-linked autosomal recessive LHON in a young male and a female originating from Estonia. The patients presented severe loss of central vision and clinical features indistinguishable from mitochondrial LHON. The whole exome sequencing carried out in the male patient and the next-generation sequencing panel in the young female patient identified the same homozygous missense variant in the DNAJC30 gene. Our cases further reinforce the pathogenicity of c.152A > G, p.(Tyr51Cys) DNAJC30 variant causing autosomal recessive LHON. According to the gnomAD database, the allele frequency of this variant in the Estonian population is 0.8%, translating into a prevalence of carriers of 1:60. It is the highest among different gnomAD populations. Applying the Hardy-Weinberg equation, an estimated 92 persons in the Estonian population carry the homozygous variant c.152A > G, p.(Tyr51Cys) in DNAJC30. In patients with LHON, we advise sequencing both the DNAJC30 gene and mitochondrial DNA simultaneously.

Large gene panel sequencing in clinical diagnostics-results from 501 consecutive cases.

BACKGROUND: In addition to whole exomes, large gene panels of clinically associated genes are used as high-throughput sequencing tests in many clinical centers, but their clinical utility has been much less investigated. MATERIALS AND METHODS: Here we report the results of the 501 first unselected cases for whom TruSight One panel (Illumina Inc., San Diego, California) was sequenced as a clinical diagnostic test for a variety of indications in our department. The analysis was restricted to virtual subpanels based on referral forms, where doctors were asked to list candidate genes or select one from predefined larger panels. RESULTS: A probable or definite pathogenic finding was reported in 26.3% of cases. In 238 samples for whom 1 to 9 genes were requested for analysis, the diagnostic yield was significantly higher compared to other 263 cases for whom larger subpanels were requested (31.5% vs 21.7%, respectively, P = .016). Detected mutations included single nucleotide variants, small insertions and deletions, and larger copy number variants. Out of 157 reported mutations, 67 were previously undescribed. CONCLUSION: The clinical utility of large gene panel sequencing in the context of other genetic diagnostic tests is discussed in detail.