ClinVar Genomic variation as it relates to human health

Abnormal cerebral white matter morphology (present) , Joint hypermobility (present) , Seizure (present) , Transient global amnesia (present) , Transient ischemic attack (present) , Macule (present) (less)

In 28 patients with autosomal recessive Leber-like hereditary optic neuropathy (LHONAR1; 619382) from 26 families, including 2 sib pairs, and in 1 patient with a clinical diagnosis of Leigh syndrome (see 256000), Stenton et al. (2021) identified homozygosity for a c.152A-G transition (c.152A-G, NM_032317.2) in the DNAJC30 gene, resulting in a tyr51-to-cys (Y51C) substitution in the conserved J domain that leads to degradation of the protein. The mutation was identified by a combination of whole-exome and Sanger sequencing. The mutation was present in the gnomAD database with an allele frequency of 0.125%. Mitochondrial complex I activity was defective in patient-derived fibroblasts, and mitochondrial complex I respiration was reduced in patient-derived muscle tissue. Introduction of wildtype DNAJC30 in patient fibroblasts rescued the complex I respiration defect. In 28 patients from 26 additional families with LHONAR1, including 2 patients with a clinical diagnosis of Leigh syndrome and 2 patients (sibs of affected parents) who were asymptomatic, Stenton et al. (2022) identified homozygosity for the Y51C substitution in the DNAJC30 gene. Fifteen patients were from the Czech Republic, 6 from Russia, 2 from the United States, and 1 each from Romania, Poland, Turkey, Sweden, and Germany. Based on their experience with diagnostic centers for LHON, the authors estimated that the DNAJC30 variant accounts for up to 27% of genetically diagnosed LHON patients in Eastern European populations and up to 5% in nonfounder populations. In a Polish patient with LHONAR1, Zawadzka et al. (2022) identified homozygosity for the Y51C mutation in the DNAJC30 gene. The mutation, which was identified by trio whole-exome sequencing, was present in the gnomAD database (v3.1.1) at an allele frequency of 0.001097. In 2 sibs with LHONAR1, Zawadzka et al. (2022) identified compound heterozygous mutations in the DNAJC30 gene, Y51C and a 2-bp deletion (c.130_131del; 618202.0004) predicted to result in a frameshift and premature termination. The mutations, which were identified by whole-exome sequencing, segregated with disease in the family. The deletion was present in the gnomAD database (v.3.1.1) at an allele frequency of 0.00001314. In fibroblasts from one of the sibs, complex I activity was reduced. The authors noted that both sibs also carried a heterozygous mutation in the NDUFS8 gene (c.484G-T, V162L), which was classified as a variant of unknown significance. In 2 unrelated Estonian patients with LHONAR1, Mauring et al. (2023) identified homozygosity for the Y51C mutation in the DNAJC30 gene. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing in patient 1 and by next-generation sequencing in patient 2. The mutation in family 1 was found to segregate with the disorder. The mutation was present in the gnomAD database at an allele frequency of 0.8% in the Estonian population. In 30 European patients, including 2 sib pairs, with LHONAR, Kieninger et al. (2022) identified homozygosity for the Y51C mutation in the DNAJC30 gene. The mutation was identified by sequencing of the gene. In 3 additional, unrelated European patients with LHONAR, Kieninger et al. (2022) identified compound heterozygosity for 2 mutations in the DNAJC30 gene: Y51C and a c.610G-T transition, resulting in a glu204-to-ter (E204X; 618202.0005) substitution upstream of the transmembrane domain. The mutations were identified by sequencing of the DNAJC30 gene. Allelic mapping showed that the mutations were in trans in all 3 patients. (less)