Homozygous GUCY2D Variant Linked to Blindness in Iranian Family

Researchers have identified a homozygous missense variant in the GUCY2D gene in an Iranian patient with severe visual impairment consistent with Leber congenital amaurosis (LCA), a genetically heterogeneous group of inherited retinal disorders that typically follows an autosomal recessive inheritance pattern and begins in infancy or early childhood. The study, published in BMC Medical Genomics, combines genetic analysis with computational structural modeling to explore the possible molecular consequences of the variant.

To find the causal variant, the team employed whole-exome sequencing 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 then carried out in the proband, both parents, and a clinically unaffected sister to confirm the variant and assess how it segregated within the family.

The sequencing effort identified a homozygous missense variant in GUCY2D, NM_000180.4:c.2944G>A, p.(Gly982Ser), in the proband, and Sanger sequencing confirmed its presence. The variant had previously been reported in a Kurdish child with LCA1, making the present study an independent observation of the same variant in another Kurdish family. Consanguinity in the family is consistent with the autosomal recessive pattern expected for this condition, and the unaffected sister’s status helped demonstrate segregation of the variant within the pedigree.

Beyond the genetic findings, the researchers turned to structural modeling to probe what the amino acid substitution might do to the protein. They modeled both the wild-type and the p.(Gly982Ser) GUCY2D proteins, then performed molecular docking analysis with GTP using AutoDock Vina, evaluating the docking results to explore potential structural differences between the two protein versions.

The docking results were deliberately cautious in their interpretation. Exploratory molecular docking revealed model-dependent differences in GTP pose sampling between the wild-type and G982S forms of 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. In other words, the computational signals were suggestive but not conclusive.

The authors conclude that the study reports an independent observation of the homozygous GUCY2D p.(Gly982Ser) variant in a patient with a clinical presentation consistent with LCA. They state that the genetic findings and computational analyses provide additional context for understanding the potential molecular effects of the variant, but that further experimental functional studies are required to determine its biological consequences and its contribution to LCA1 pathogenesis.

The work illustrates both the power and the limits of current approaches to rare inherited retinal disease. Computational tools such as docking can generate hypotheses about how a substitution alters protein function, but as this study shows, scoring uncertainties and modeling assumptions mean such predictions require laboratory validation before they can be treated as established mechanisms.

For families affected by LCA, each independently confirmed observation of a variant adds to the evidence base connecting specific genetic changes to specific clinical presentations.

Subject of Research: A homozygous GUCY2D missense variant identified in an Iranian family with Leber congenital amaurosis, analyzed by genetic sequencing and molecular docking

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

Article References: Alimoradi, E., Tabar, S. S., Khosravi, T., Nejati, P., Favaedi, M., Tabar, H. A., Oladnabi, M., & Alibakhshi, R. (2026). A homozygous missense variant in the GUCY2D gene associated with Leber congenital amaurosis in an Iranian family: molecular docking insights and genetic analysis. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02500-9

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02500-9

Keywords: Leber congenital amaurosis, GUCY2D, missense variant, whole-exome sequencing, Sanger sequencing, molecular docking, autosomal recessive inheritance, consanguinity, inherited retinal disease, phototransduction, LCA1, Iranian family