Biallelic variants in are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease.

Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the strains on non-fermentable (respiratory) medium compared with wild-type , confirming the pathogenicity of the variants. We establish that is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic (Sengers syndrome) and (Barth syndrome) variants, there was no evidence of cardiomyopathy.KEYWORDSOXPHOS defect, WES/WGS, cardiolipin, mitochondria, mitochondrial disease, mitochondrial phospholipid© 2022 The Authors.