GUCY2D – Central Areolar Choroidal Dystrophy

Central areolar choroidal dystrophy (CACD) is a rare macular dystrophy characterized by progressive central visual loss. A systematic review identified GUCY2D among six genes implicated in monogenic dominant CACD pathogenesis (PMID:35656327). Deep sequencing in a large Northern Irish pedigree revealed a heterozygous c.2798T>C (p.Val933Ala) variant in GUCY2D that co-segregated with CACD in all affected family members (PMID:22695961). This missense substitution occurs within the catalytic domain of retinal guanylyl cyclase 1 (RetGC1) at a highly conserved residue and is predicted to disrupt cGMP synthesis.

Although functional assays specific to p.Val933Ala have not been reported, pathogenic GUCY2D variants in the catalytic domain are well known to impair RetGC1 activity, leading to cone and rod dysfunction. No conflicting genetic or phenotypic data have been described for GUCY2D in CACD. Together, available data support a Limited clinical validity for GUCY2D–CACD association based on a single segregating kindred with a novel catalytic-domain variant and bioinformatic concordance.

Key Take-home: Include GUCY2D catalytic-domain variants, such as p.Val933Ala, in genetic testing panels for CACD to inform diagnosis and management.

References

• Frontiers in genetics • 2022 • New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates. PMID:35656327
• Investigative ophthalmology & visual science • 2012 • A novel GUCY2D mutation, V933A, causes central areolar choroidal dystrophy. PMID:22695961

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