ClinVar

In 2 unrelated probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Shukla et al. (2017) identified a homozygous c.259G-A transition (c.259G-A, NM_030940.3) in exon 4 of the ISCA1 gene, resulting in a glu87-to-lys (E87K) substitution at a conserved residue in the Fe-S biogenesis domain. Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was not found in homozygous state in the 1000 Genomes Project or the Exome Variant Server databases or in an in-house exome database of 139 individuals from the same population; however, the variant was found at very low frequencies in heterozygous state in the ExAC and gnomAD databases. Both probands had a similarly affected sib, although biologic material was not available from the sibs. All of the children were deceased at the time of the report. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed.