PET100 – Cytochrome-c Oxidase Deficiency Disease

This summary details the association between PET100 (HGNC:40038) and cytochrome-c oxidase deficiency disease (MONDO:0009068). Multiple independent studies have identified pathogenic PET100 variants in patients presenting with isolated complex IV deficiency, a biochemical hallmark of cytochrome-c oxidase deficiency. The evidence is derived from case reports, familial studies, and functional assessments that collectively support a strong gene‑disease relationship.

The clinical validity of the association is classified as Strong based on genetic evidence from a truncating variant observed in a neonatal‐onset case (PMID:25293719) and additional evidence from two families with variant segregation (PMID:31406627). These studies together provide evidence from both isolated probands and family-based analyses, meeting critical ClinGen criteria.

Genetic evidence supports an autosomal recessive inheritance pattern. In affected families, segregation analysis revealed additional affected relatives carrying the PET100 variants. Key variant observations include the homozygous truncating mutation c.142C>T (p.Gln48Ter), as well as reported missense and initiation codon changes. The genetic data, including variant types and segregation in multiple families, further substantiate the association.

Functional studies have provided moderate evidence by demonstrating that the c.142C>T (p.Gln48Ter) mutation abolishes PET100 activity, resulting in a complete loss of cytochrome c oxidase activity and disruption of holocomplex assembly. These findings from in vitro assays and model systems recapitulate the human biochemical phenotype and support a loss‑of‑function mechanism.

The clinical phenotype associated with PET100 variants includes symptoms such as seizures, lactic acidosis, hypotonia, developmental regression, respiratory insufficiency, global developmental delay, and failure to thrive. The overlap between these clinical features and the biochemical defect in cytochrome-c oxidase function reinforces the diagnostic clinical utility of identifying PET100 mutations.

In summary, robust clinical genetic data combined with supportive functional evidence strongly implicate PET100 mutations in cytochrome-c oxidase deficiency disease. Key take‑home: PET100 should be considered in the diagnostic workup for patients with mitochondrial dysfunction manifesting with complex IV deficiency, aiding in precise prognostication and management.

References

• European journal of human genetics : EJHG • 2015 • A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency PMID:25293719
• Journal of pediatric genetics • 2019 • The Lebanese Allele in the PET100 Gene: Report on Two New Families with Cytochrome c Oxidase Deficiency PMID:31406627

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