A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

ABSTRACT

Background: Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD), are primary causes of inherited childhood blindness. Both are autosomal recessive diseases, with mutations in more than 25 genes explaining approximately ~70% of cases. However, the genetic cause for many cases remains unclear. Sequencing studies from genetically isolated populations with increased prevalence of a disorder has proven useful for rare variant studies, making Costa Rica an ideal place to study LCA/EORD genetics.

Materials and Methods: Twenty-eight affected children (25 LCA, three EORD) and their immediate family members, totaling 52 individuals (30 affected) from 22 families, were sequenced. Whole exome sequencing was performed on all affected individuals. Available parents were analyzed either by whole exome sequencing (WES) or Sanger sequencing to determine transmission.

Results: All affected individuals demonstrated compound heterozygous or homozygous mutations in known Inherited Retinal Disease (IRD) associated genes. Twelve variants were identified in at least one individual in three genes, RDH12, RPE65, and USH2A. Four recurrent RPE65 mutations were observed in 97% of individuals and 95% of families. All patients with LCA and two of the three individuals with EORD had biallelic mutations in RPE65; one child with EORD had a homozygous RDH12 mutation.

Conclusions: These data suggest that the majority of LCA/EORD in Costa Rica is due to four founder mutations in RPE65 which have been maintained in this genetically isolated population. This finding is of great clinical significance due to the availability of gene therapy recently approved in the US and European Union for patients with biallelic RPE65 defects.

KEYWORDS:

• RPE65
• Costa Rica
• Leber congenital amaurosis
• inherited retinal disease

Acknowledgments

The authors wish to thank all patients and their families for their cooperation. The authors would like to thank Jennifer Schulte for her technical support. This study was supported in part by the Genomic Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Supplemental Materials

Supplemental data for this article can be accessed at https://doi.org/10.1080/13816810.2019.1582069.

Additional information

Funding

This work was supported by the Research to Prevent Blindness, New York, NY, the Medical University of South Carolina Center for Genomic Medicine, Charleston, SC, the Medical University of South Carolina Center for Global Health, Charleston, SC, and the Medical University of South Carolina Hollings Cancer Center Genomic Shared Resource, Charleston, SC.