COQ5 – Neurodevelopmental Disorder

COQ5 encodes a C-methyltransferase critical for coenzyme Q10 (CoQ10) biosynthesis and interacts with the poly(A)-tail regulator ZC3H14 during neural development. Biallelic pathogenic variants in COQ5 cause an autosomal recessive neurodevelopmental disorder with systemic CoQ10 deficiency.

Genetic analysis of a fifth patient identified compound heterozygosity for a canonical splice-site mutation, c.681+1G>A, and a recurrent missense change, supporting autosomal recessive inheritance with 5 probands across 3 families (PMID:37599337). No additional affected relatives were reported in these pedigrees.

Affected individuals share a core phenotype of intellectual disability (HP:0001249), encephalopathy (HP:0001298), cerebellar ataxia (HP:0001251), cerebellar atrophy (HP:0001272), speech regression or dysarthria, short stature (HP:0004322), and global developmental delay. Additional features include microcephaly (HP:0000252), dysmorphic facies, and regressive social faculties.

Functional studies confirm that c.681+1G>A leads to aberrant COQ5 mRNA splicing and reduced full-length transcript levels in patient cells (PMID:37599337). In human 143B cells, COQ5 knockdown decreases CoQ10 content and destabilizes a high-molecular-weight COQ5-containing complex (PMID:32194061), and FCCP-treated or MERRF mutant cybrids show impaired COQ5 maturation with reduced CoQ10 levels (PMID:27155576).

The concordant genetic and biochemical data demonstrate loss of COQ5 function as the pathogenic mechanism in this neurodevelopmental syndrome. The reproducible genotype–phenotype correlation and mechanistic assays support a ClinGen Strong gene–disease association.

Key take-home: Biallelic COQ5 mutations underlie a treatable autosomal recessive neurodevelopmental disorder via CoQ10 deficiency, guiding genetic diagnosis and potential CoQ10 supplementation.

References

• Journal of applied genetics • 2023 • Congenital coenzyme Q5-linked pathology: causal genetic association, core phenotype, and molecular mechanism. PMID:37599337
• Biochimica et biophysica acta • 2016 • Disruption of the human COQ5-containing protein complex is associated with diminished coenzyme Q10 levels under two different conditions of mitochondrial energy deficiency. PMID:27155576
• Biochimica et biophysica acta. Bioenergetics • 2020 • Characterization of human mitochondrial PDSS and COQ proteins and their roles in maintaining coenzyme Q10 levels and each other's stability. PMID:32194061

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