A high prevalence of biallelicRPE65mutations 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 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 WES or Sanger sequencing to determine transmission. Results: All affected individuals demonstrated compound heterozygous or homozygous mutations in known Inherited Retinal Disease (IRD) 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 effects 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 US and European Union for patients with biallelic RPE65 deficits.

RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 45 affected patients

“…A total of 212 pathogenic variants in RPE65 have been reported to date (HGMD, [17]), of which the majority are missense (54.71%), followed by nonsense-frameshift (32.54%) and splice site variants (12%). A similar frequency of the type of mutation was observed in our cohort (57%, 28% and 11%, respectively); thus, our cohort is representative of the first described in LCA patients from India [15] and Central America [45], being related to more severe phenotypes. Interestingly, p.(Ile98Hisfs*26) seems to represent a founder mutation in our cohort with all the carriers families sharing a common haplotype.…”

“…By contrast, the most common alleles found in our cohort were p.(Ile98Hisfs*26, p.(Pro111Ser) and p.(Gly187Glu). The p.(Ile98Hisfs*26) variant was first described in LCA patients from India [15] and Central America [45], being related to more severe phenotypes. Interestingly, p.(Ile98Hisfs*26) seems to represent a founder mutation in our cohort with all the carriers families sharing a common haplotype.…”

“…Interestingly, p.(Ile98Hisfs*26) seems to represent a founder mutation in our cohort with all the carriers families sharing a common haplotype. Due to the historical influence of the Spanish ancestry in Central and South America populations, this finding could be related to the enrichment of this rare variant in the Latino cohort of GnomAD and to its increased frequency in LCA patients from Costa Rica where this variant was reported as a recurrent mutation [45]. The variant p.(Pro111Ser), which is carried by 3 of our families, were first described in our cohort of patients, as recently we reported [25].…”

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…Similarly, EYS gene variants were found to be causative in 51% of a RP cohort from Japan [ 36 ]. This discovery is not unique, as several other parallel studies have revealed similar founder mutations in their target populations, for example, Belgium, RAX2 [ 37 ]; Costa Rica, RPE65 [ 38 ]; Finland, CERKL [ 39 ]; Japan, EYS [ 36 ]; Spain, RP1 [ 40 ] and ABCA4 [ 41 ]; Jewish community in Caucasia, PDE6B [ 42 ]; Pakistan, ABCA4 and NMNAT1 [ 43 ]; Guyana, BBS9 [ 44 ]; and Faroe Islands, MERTK [ 45 ]. The enrichment of these variants, several of which are large structural variants, emphasises the value of population-specific TS panels to target and detect mutations and mutational breakpoints that may be missed by commercial generic gene panel sequencing or even WES.…”

Recent Developments on the major genes involved in retinitis pigmentosa

“…2,6,75 Over 100 mutations are associated with the pathogenesis of arLCA, 2,6,75-78 RP. 6,[75][76][77] adult onset vitelliform macular dystrophy 79 and CRD. 80 Although it may produce both adRP and arRP, it is mostly associated with arRP.…”