Severe congenital lactic acidosis and hypertrophic cardiomyopathy caused by an intronic variant in NDUFB7

Mutations in structural subunits and assembly factors of complex I of the oxidative phosphorylation system constitute the most common cause of mitochondrial respiratory chain defects. Such mutations can present a wide range of clinical manifestations, varying from mild deficiencies to severe, lethal disorders. We describe a patient presenting intrauterine growth restriction and anemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Whole genome sequencing revealed an intronic biallelic mutation in the NDUFB7 gene (c.113-10C>G) and splicing pattern alterations in NDUFB7 messenger RNA were confirmed by RNA Sequencing. The detected variant resulted in a significant reduction of the NDUFB7 protein and reduced complex I activity. Complementation studies with expression of wild-type NDUFB7 in patient fibroblasts normalized complex I function. Here we report a case with a primary complex I defect due to a homozygous mutation in an intron region of the NDUFB7 gene.

Automated summary

In this case, a patient with a homozygous mutation in an intron region of the NDUFB7 gene had a primary complex I defect, presenting symptoms such as intrauterine growth restriction, hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and eventually leading to fatal outcome. The detected mutation resulted in reduced NDUFB7 protein levels and complex I activity, which were normalized through complementation studies with wild-type NDUFB7 expression in patient fibroblasts.