The co-occurrence of homozygous variants in GUCY2D and MYO7A in Leber congenital amaurosis associated with deafness: clinical, molecular, and in silico investigation.

Leber congenital amaurosis (LCA) is a severe early-onset inherited retinal disorder characterized by congenital or very early blindness, most frequently resulting from autosomal recessive mutations in retinal disease genes. Here, we describe a 7-year-old boy born to consanguineous parents who presented with early-onset profound visual impairment and severe bilateral sensorineural hearing loss, global developmental delay, and hypotonia. Ocular examination showed congenital nystagmus, absent light perception, and non-recordable ERG/VEP despite a normal fundus, consistent with Leber congenital amaurosis. Whole‑exome sequencing, followed by segregation analysis and in‑depth bioinformatic evaluation, identified two homozygous missense variants, c.2338T > C in GUCY2D and c.2489G > A in MYO7A. Each parent was heterozygous for both variants, consistent with autosomal recessive inheritance in a consanguineous context, a pattern frequently seen in LCA cohorts. In silico prediction, conservation analysis, and protein structural modeling suggested that both variants are damaging and destabilize their respective proteins. The GUCY2D variant is expected to alter calcium‑regulated cGMP synthesis in photoreceptors, a well‑established mechanism in LCA1. The MYO7A change lies within the IQ calmodulin‑binding neck domain, potentially disturbing interactions critical for hair‑cell function, in line with MYO7A's known role in sensorineural hearing loss. Taken together, the co-occurrence of homozygous variants in GUCY2D (LCA) and MYO7A (deafness) provides a plausible explanation for this unusual, severe combined phenotype, and illustrates how multilocus involvement can modulate clinical expression in inherited retinal dystrophies.