Mitochondrial diseases masks revealed on WES/WGS analysis.

Background. In clinical practice mitochondrial diseases are known to be one of the most difficult groups of the inborn errors of metabolism. Clinical heterogeneity due to large genetic variety and specific molecular features often cause overlap between different syndromes within a group. Furthermore mitochondrial disorders may be due to the failure of various other processes in the cell due to hereditary and non-hereditary factors, which manifests itself with similar clinical symptoms with primary mitochondrial pathology. We present 5 cases in which physicians had a great suspicion of primarily mitochondrial disease, but further WES/WGS analysis revealed pathogenic variants in genes not playing the direct role in maintenance of mitochondrial functions. Methods. The causative nucleotide variants were revealed on WES in 3 cases, on WGS in 2 cases. Results. Paying much attention to individual clinical symptoms physicians often follow the wrong direction in searching primarily mitochondrial disorder. NGS showed many other inherited disorders presenting as mitochondrial “masks”. We present our own examples: patient 1 with sporadic pathogenic MORC2 variant presented with profound hypotonia, seizure, Leigh-like brain MRI lesions, lactic acidosis; patient 2 with sporadic pathogenic HK1 variant had optic disk pallor, ataxia, dystonia, basal ganglia involvement; patient 3 with RANBP2 pathogenic variant presented with acute encephalopathy, optic atrophy, thalamic lesions on MRI; patient 4 with two heterozygous pathogenic variants in PRF1 showed hepatosplenomegaly, jaundice, seizure, lactic acidosis, leukopenia, thrombocytopenia; patient 5 with two novel compound heterozygous variants in VPS13D suffered from ataxia, speech delay, epilepsy and basal ganglia involvement.