PDE6H – Achromatopsia

PDE6H encodes the inhibitory γ-subunit of cone cyclic guanosine monophosphate phosphodiesterase, a key component of cone phototransduction. Biallelic loss-of-function variants in PDE6H cause autosomal-recessive incomplete achromatopsia, a cone dysfunction disorder characterized by color vision defects, photophobia, nystagmus, and severely reduced visual acuity.

In a cohort of 611 index cases with achromatopsia, a homozygous nonsense variant c.35C>G (p.Ser12Ter) in PDE6H was identified in three affected individuals from two independent families (PMID:22901948). A subsequent report described the same homozygous c.35C>G (p.Ser12Ter) variant segregating in two affected brothers from a consanguineous Pakistani family (PMID:27472364). Together, these studies document five affected individuals across three families, confirming autosomal-recessive inheritance and robust segregation of the biallelic variant.

To date, the spectrum of PDE6H variants in achromatopsia is limited to this recurrent nonsense change. No additional missense or splice variants have been reported in achromatopsia cohorts, suggesting a founder or hotspot effect for c.35C>G (p.Ser12Ter). Carrier frequency and population distribution remain to be elucidated through broader screening.

Functional support includes immunohistochemical colocalization in mouse retina demonstrating uniform Pde6h expression in all cone photoreceptors, consistent with its role in cone signal transduction (PMID:22901948). No animal knockout or rescue models have yet been described.

Loss of PDE6H inhibitory function likely leads to dysregulated cGMP hydrolysis, cone photoreceptor dysfunction, and incomplete achromatopsia. The phenotype remains stationary with respect to acuity, although symptoms manifest in infancy.

Integration of genetic and experimental data supports a Moderate ClinGen classification. PDE6H should be included in diagnostic panels for autosomal-recessive achromatopsia, enabling precise molecular diagnosis, genetic counseling, and selection of candidates for emerging gene therapies.

References

• American journal of human genetics • 2012 • A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia PMID:22901948
• Genes • 2016 • Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan PMID:27472364

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