A homozygous missense variant in the GUCY2D gene associated with Leber congenital amaurosis in an Iranian family: molecular docking insights and genetic analysis

Leber congenital amaurosis encompasses a genetically heterogeneous spectrum of inherited retinal disorders, typically following an autosomal recessive inheritance pattern, with onset in infancy or early childhood. Several genes have been associated with LCA, including GUCY2D , which encodes retinal membrane guanylyl cyclase involved in phototransduction. Whole-exome sequencing was employed to identify candidate variants in an Iranian proband from a consanguineous family presenting with severe visual impairment consistent with LCA. Variant interpretation was performed using database resources and in silico prediction tools. Sanger sequencing was performed in the proband, both parents, and the clinically unaffected sister to confirm the variant and assess its segregation within the family. Structural modeling of wild-type and p.(Gly982Ser) GUCY2D proteins was performed, followed by molecular docking analysis with GTP using AutoDock Vina. Docking results were evaluated to explore potential structural differences between the wild-type and mutant proteins. A homozygous missense variant in GUCY2D , NM_000180.4:c.2944G > A, p.(Gly982Ser), was identified in the proband and confirmed by Sanger sequencing. This variant has previously been reported in a Kurdish child with LCA1, and the present study represents an independent observation in a Kurdish family. Exploratory molecular docking revealed model-dependent differences in GTP pose sampling between wild-type and G982S GUCY2D. However, the observed Vina-score differences were small relative to the uncertainty of the scoring function, and no retained pose simultaneously satisfied all predefined catalytic-geometry criteria. This study reports an independent observation of the homozygous GUCY2D p.(Gly982Ser) variant in a patient with a clinical presentation consistent with LCA. The genetic findings and computational analyses provide additional context for understanding the potential molecular effects of this variant. However, further experimental functional studies are required to determine its biological consequences and contribution to LCA1 pathogenesis.