Whole-Exome Sequencing Identifies a Variant of the Mitochondrial MT-ND1 Gene Associated with Epileptic Encephalopathy: West Syndrome Evolving to Lennox–Gastaut Syndrome

We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox–Gastaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole-exome sequencing (WES) uncovered two heterozygous mutations in NDUFV2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT-ND1 (MTND1) gene (m.3946G>A, p.E214K). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III₂/IV and I/III₂), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.

Human Mutation November 2013