Clinical application of whole exome sequencing reveals a novel compound heterozygous TK2-mutation in two brothers with rapidly progressive combined muscle-brain atrophy, axonal neuropathy, and status epilepticus.

Mutations in several genes cause mtDNA depletion associated with encephalomyopathy. Due to phenotypic overlap, it is difficult to conclude from clinical phenotype to genetic defect. Here we report on two brothers who presented with rapid fatty muscle degeneration, axonal neuropathy, rapid loss of supratentorial white and gray matter, and status epilepticus. Whole exome sequencing coupled with 'identity-by-state' (IBS) analysis revealed a compound heterozygous missense mutation (p.M117V, p.A139V) in the thymidine kinase 2 (TK2) gene that segregated with the phenotype. Both mutations were located in the thymidine binding pouch of the enzyme. Residual mtDNA copy numbers in muscle were 8.5%, but normal in blood and fibroblasts. Our results broaden the clinical phenotype spectrum of TK2 mutations and promote WES as a useful method in the clinical setting for mutation detection, even in untypical cases. If two or more affected siblings from a non-consanguineous family can be investigated, IBS-analysis provides a powerful tool to narrow the number of disease candidates, similarly to autozygosity mapping in consanguineous families.