Introduction: Leber congenital amaurosis (LCA) is one of the most severe eye dystrophies characterized by severe vision loss at an early stage and accounts for approximately 5% of all retinal dystrophies. The genetic basis of LCA is highly heterogeneous and to date, more than 25 genes have been implicated in the pathogenesis of LCA. Investigating genes and related mutation in heterogeneous disorders by conventional methods is time- and cost-consuming. This study aimed to use WES to investigate an Iranian family with a member affected by LCA.
Methods: The present study reported a novel frameshift mutation c.459delC in the lecithin retinol acyltransferase (LRAT) gene associated with early onset retinitis pigmentosa. We used a combination of WES and detailed family segregation analysis to identify the underlying genetic defect. Segregation analysis showed that the proband’s parents were heterozygous carriers, which is consistent with an autosomal recessive inheritance pattern, while the mutation was not found in proband wife.
Results: LRAT is necessary for producing 11-cis-retinol and regeneration of the chromophore needed for rhodopsin and cone photopigments. Deficiency in LRAT causes a lack of the 11-cis-retinal chromophore and lead to lower levels of functional visual pigment and causing severe vision problems. The identified mutation highlights the critical role of LRAT in retinal health and disease.
Conclusion: Our research demonstrates how effective next-generation sequencing (NGS) technologies are in detecting rare genetic mutations that cause hereditary retinal dystrophy. This study also emphasizes the critical role of genetic diagnosis in early intervention and management of LCA. By identifying the exact genetic mutations involved, we can develop targeted gene therapies, which could help preserve vision and enhance the quality of life for those affected. This research adds to the growing list of mutations found in the LRAT gene and highlights the importance of genetic analysis in understanding the causes of LCA. It also paves the way for future treatments, like gene replacement and editing techniques, which offer hope for conditions such as LCA.