Discovery of rare and novel variants in inherited retinal disorders: Exome sequencing analysis of six Iranian families

Abstract

Inherited retinal disorders (IRDs) are genetically heterogeneous vision disorders, including conditions such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and congenital achromatopsia. This study aimed to identify the underlying genetic causes of IRDs in six consanguineous Iranian families. We performed whole-exome sequencing (WES) on probands from six families with IRDs. Putative pathogenic variants were validated and analyzed for segregation in family members using Sanger sequencing. We identified six homozygous, likely causative variants in five distinct IRD- associated genes. A novel frameshift variant, c.408delG (p.Val136fs), in CNGB3 led to a definitive diagnosis of achromatopsia in one family, revising the initial clinical impression. A novel missense variant, c.G1216A (p.Glu406Lys), was identified in IFT140 in a patient with RP. Previously reported pathogenic variants were found in TULP1 (c.1199G>A; p.Arg400Gln) and MERTK (c.392G>A; p.Trp131Ter) in two families with RP. In two other families with LCA, we identified known pathogenic variants in RPE65 (c.1088C>G; p.Pro363Arg and c.858+1delG). All variants segregated with the disease in an autosomal recessive pattern. Our findings expand the mutational spectrum of IRDs and highlight the crucial role of WES in providing precise molecular diagnoses, which can refine clinical classifications and inform genetic counseling. The identification of two novel variants underscores the importance of studying underrepresented populations, such as that of Iran, to fully characterize the genetic architecture of these disorders.