The application of DNA sequencing has led to tremendous progress in our understanding and diagnosis of mitochondrial disease, with mutations in hundreds of genes now established as causes. However, the now-standard screening of hundreds of candidate genes one at a time yields a genetic diagnosis less than half the time. For the sake of the majority of mitochondrial disease patients, who suffer both from persistent medical uncertainty and from denial of care available to those with genetic diagnoses, we urgently need to figure out why. This study adds to the growing evidence that the single-gene paradigm of mitochondrial disease fails for many patients, and that more complex modes of inheritance will help to explain that shortfall.
This subject in this study is an extremely disabled six-year-old boy. The admirably exhaustive analysis of his illness revealed, among other things, pathogenic mutations in three separate genes. Each gene was previously known to harbor other pathogenic variants in other Leigh’s patients, and was thus a likely suspect a priori.
In each instance, the mutant was paired with a normal variant. This is a bit surprising, as the inheritance of Leigh syndrome is most often autosomal recessive. It seems likely, though not conclusively proven here, that disease in this case is a cumulative effect of multiple mutations, each only mildly deleterious, such that no one of these heterozygotes by itself could have caused the observed symptoms.
As the authors summarize, “Recently, oligogenic inheritance of heterozygous variants has increasingly been recognized as a pathogenic mechanism underlying complex phenotypes of metabolic myopathies and mitochondrial neurodegenerative diseases with a deficit in energy metabolism…Thus, our study extends the traditional approach of a single-gene disorder linked to mitochondrial inborn errors of metabolism diseases with the concept of multiple heterozygous variants mapping in genes known to cause monogenic metabolic disorders.”