Am J Med Genet A. 2026 Aug 26.
COX14 encodes a transmembrane protein essential for cytochrome c oxidase (COX) complex assembly. A homozygous missense variant in COX14 was reported in three siblings from a single consanguineous family with severe, fatal infantile mitochondrial complex IV deficiency nuclear type 10 (MC4DN10; MIM# 619053). No additional cases have been identified since, and the ClinGen Mitochondrial Disease Gene Curation Expert Panel classified the COX14-MC4DN10 gene-disease association as having limited evidence. We report a 9-year-old male with biallelic COX14 variants (c.82delT, p.Tyr28Thrfs*83, and c.3G>A, p.Met1?) representing the second unrelated family with MC4DN10. In contrast to the fatal neonatal course previously described, this individual demonstrates an attenuated encephalomyopathic phenotype with prolonged survival. Initial presentation at 6 months included hypotonia, feeding difficulties, and developmental delay. Previously unreported features included growth hormone deficiency, ascending aortic dilation, and distinct neuroradiological findings. At age 8 years, he developed neurological regression and ataxia with brain MRI findings consistent with Leigh syndrome. Muscle biopsy confirmed reduced COX enzymatic activity (33% of mean). Identification of a second unrelated family with biallelic COX14 variants and biochemically confirmed complex IV deficiency strengthens the gene-disease association for MC4DN10. This individual presents an attenuated encephalomyopathic phenotype with novel endocrine and cardiovascular manifestations, underscoring the importance of genomic evaluation in suspected mitochondrial disorders even in the absence of classic biochemical markers such as lactic acidosis.
Keywords:
COX14
; Leigh syndrome; MC4DN10; ascending aortic dilation; cytochrome c oxidase deficiency; encephalomyopathy; growth hormone deficiency; mitochondrial complex IV deficiency nuclear type 10