Rationale for the study Cardiomyopathy is an increasingly recognised presentation of mitochondrial disease in infancy. This may be an isolated finding or part of a wider multisystem disease presentation. Isolated deficiency of respiratory chain complex I is the most commonly identified biochemical defect in paediatric mitochondrial disease. Here we used a candidate gene and homozygosity mapping approach to identify the causative gene defect in two children with complex I deficiency and cardiomyopathy.

Methodology Complex I assembly was investigated in a cohort of children with isolated complex I deficiency using Blue Native polyacrylamide gel electrophoresis (BN-PAGE). An integrative genomics approach, combining homozygosity mapping and candidate gene and bioinformatics analyses, was used to search for the presumed nuclear gene defect in these patients.

Results BN-PAGE analysis provided evidence of defective assembly of the complex I holoenzyme in several patients. Two patients were shown to have cardiomyopathy caused by mutations in two different complex I assembly factor genes. The mutations segregated with disease in each family and were absent in >200 control alleles. Western blot analysis demonstrated reduced steady-state level of the mutated proteins, and lentiviral rescue was used to confirm the genetic defect in one case.

Conclusions Mitochondrial complex I deficiency is an important cause of infantile-onset cardiomyopathy. This disorder is extremely genetically heterogeneous, but identification of the precise genetic defect is important, since this will inform treatment options, provide more accurate information regarding recurrence risks, and allow prevention of further cases by prenatal or preimplantation genetic diagnosis.