Neonatal mitochondrial encephalopathy due to a splice-altering variant in COX16
TL;DR
Two siblings born to consanguineous parents who presented with neonatal hypotonia, respiratory failure, lactic acidosis and early death are described, establishing the pathogenicity of a splice-altering COX16 variant and expanding the genetic and phenotypic spectrum of COX16 -related mitochondrial disease.
Abstract
COX16 is a nuclear-encoded assembly factor essential for mitochondrial cytochrome c oxidase (complex IV) biogenesis. Only two patients with COX16-related disease have previously been reported. We describe two siblings born to consanguineous parents who presented with neonatal hypotonia, respiratory failure, lactic acidosis and early death. Neuroimaging revealed diffuse white matter abnormalities; neither had cardiac involvement. Muscle and fibroblast studies demonstrated isolated complex IV deficiency. Whole-exome sequencing identified a novel homozygous intronic COX16 variant (c.70-11_70-8del), extremely rare in population databases and observed only in the heterozygous state and predicted to have minimal splicing impact. Reverse transcription-PCR and long-read complementary DNA sequencing confirmed complete exon 2 skipping in patient fibroblasts. Blue native polyacrylamide gel electrophoresis showed defective complex IV assembly. These findings establish the pathogenicity of a splice-altering COX16 variant and expand the genetic and phenotypic spectrum of COX16 -related mitochondrial disease. Our report underscores the importance of transcript-level assays when in silico predictions are inconclusive and highlights the usefulness of integrated genomic and functional approaches.