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This summary evaluates the association between COX6A1 (HGNC:2277) and cytochrome‑c oxidase deficiency disease (MONDO_0009068). The evidence is drawn from a classical case report of a newborn with muscle pathology and mitochondrial ultrastructural abnormalities (PMID:2175684), as well as a multi‑patient genetic screening study in 60 unrelated Czech children with COX deficiency (PMID:22592081). Together, these studies underline an association that, while not supported by extensive segregation data, is nonetheless of clinical relevance.
The clinical validity is assessed as Moderate based on the presence of evidence from both single‐patient reports and larger cohort analyses. The case report documented a newborn with severe hypotonia and mitochondrial structural disruption, and the screening study identified novel variants across several nuclear genes involved in cytochrome‑c oxidase assembly, including COX6A1. This cumulative evidence, although limited in detailed segregation or functional rescue experiments, warrants further clinical and diagnostic consideration (PMID:2175684; PMID:22592081).
From a genetic standpoint, the association is bolstered by autosomal recessive inheritance as observed in the reported cohorts. Although no specific COX6A1 variant meeting the strict HGVS criteria was explicitly detailed in the published abstracts for cytochrome‑c oxidase deficiency disease, the inclusion of COX6A1 in multi‑gene screening studies indicates its participation in the disease etiology. The evidence is further supported by predicted deleterious effects, yet the exact variant spectrum remains to be fully delineated in this context.
Functional studies in the reported literature reveal biochemical and morphological abnormalities consistent with COX deficiency. Electron microscopy and Western blot analyses demonstrated disrupted myofibre structure and decreased levels of cytochrome oxidase components in affected individuals, supporting a role for COX6A1 in maintaining proper mitochondrial function. However, direct functional assays specific to COX6A1 are limited, leading to a cautious rating of functional evidence as Limited.
It is important to note that while there are additional reports linking COX6A1 mutations to distinct phenotypes such as Charcot‑Marie‑Tooth disease, these alternative disease associations do not detract from the evidence linking COX6A1 to cytochrome‑c oxidase deficiency. No significant conflicting data were identified for the cytochrome‑c oxidase deficiency context, although further studies with detailed segregation and variant-specific information could strengthen the genetic evidence.
In conclusion, the integration of case report findings, multi‑patient genetic screening, and supportive functional data positions COX6A1 as a gene of interest in cytochrome‑c oxidase deficiency disease. Although the current evidence is moderate, it provides a useful framework for diagnostic decision‑making and emphasizes the clinical utility of including COX6A1 in genetic panels for COX deficiency disorders.
Gene–Disease AssociationModerateEvidence from a case report (PMID:2175684) and a 60‑patient screening study (PMID:22592081) supports the association, though detailed segregation and variant‐specific data are limited. Genetic EvidenceModerateInclusion of COX6A1 in multi‑gene analyses and identification of novel variants among a cohort of patients implicate the gene in disease pathology despite the absence of an explicit variant description. Functional EvidenceLimitedBiochemical analyses demonstrate mitochondrial dysfunction and altered cytochrome oxidase activity, but direct functional studies on COX6A1 remain sparse. |