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

• Published in: Human mutation Vol. 42; no. 4; pp. 378 - 384
• Main Authors: Correia, Sandrina P., Moedas, Marco F., Naess, Karin, Bruhn, Helene, Maffezzini, Camilla, Calvo‐Garrido, Javier, Lesko, Nicole, Wibom, Rolf, Schober, Florian A., Jemt, Anders, Stranneheim, Henrik, Freyer, Christoph, Wedell, Anna, Wredenberg, Anna
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.04.2021
• Subjects: Acidosis; Acidosis, Lactic - genetics; Cardiomyopathy; Cardiomyopathy, Hypertrophic - genetics; Case reports; Cell- och molekylärbiologi; Complementation; cryptic splice site mutation; Electron transport; Electron Transport Complex I - genetics; Encephalopathy; Fibroblasts; Genomes; Humans; intrauterine clinical manifestations; isolated complex I deficiency; Kardiologi; Klinisk medicin; Lactic acidosis; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mitochondria; mitochondrial disease; Mitochondrial Diseases - genetics; mRNA; Mutation; NADH, NADPH Oxidoreductases - genetics; NDUFB7; Oxidative phosphorylation; Phosphorylation; Postpartum; Whole genome sequencing; cryptic splice site mutation; intrauterine clinical manifestations; NDUFB7; isolated complex I deficiency; mitochondrial disease
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.24173

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. A combination of whole genome sequencing, RNAseq, and molecular biology revealed causality for complex I deficiency.