Four Unique Genetic Variants in Three Genes Account for 62.7% of Early-Onset Severe Retinal Dystrophy in Chile: Diagnostic and Therapeutic Consequences

Int J Mol Sci. 2024 Jun 3;25(11):6151. doi: 10.3390/ijms25116151.

Abstract

Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy (EOSRD) stand as primary causes of incurable childhood blindness. This study investigates the clinical and molecular architecture of syndromic and non-syndromic LCA/EOSRD within a Chilean cohort (67 patients/60 families). Leveraging panel sequencing, 95.5% detection was achieved, revealing 17 genes and 126 variants (32 unique). CRB1, LCA5, and RDH12 dominated (71.9%), with CRB1 being the most prevalent (43.8%). Notably, four unique variants (LCA5 p.Glu415*, CRB1 p.Ser1049Aspfs*40 and p.Cys948Tyr, RDH12 p.Leu99Ile) constituted 62.7% of all disease alleles, indicating their importance for targeted analysis in Chilean patients. This study underscores a high degree of inbreeding in Chilean families affected by pediatric retinal blindness, resulting in a limited mutation repertoire. Furthermore, it complements and reinforces earlier reports, indicating the involvement of ADAM9 and RP1 as uncommon causes of LCA/EOSRD. These data hold significant value for patient and family counseling, pharmaceutical industry endeavors in personalized medicine, and future enrolment in gene therapy-based treatments, particularly with ongoing trials (LCA5) or advancing preclinical developments (CRB1 and RDH12).

Keywords: Chile; Leber congenital amaurosis (LCA); early-onset retinal dystrophy (EOSRD).

MeSH terms

  • Adolescent
  • Alcohol Oxidoreductases / genetics
  • Alleles
  • Child
  • Child, Preschool
  • Chile / epidemiology
  • Eye Diseases, Hereditary
  • Eye Proteins / genetics
  • Female
  • Genetic Variation
  • Humans
  • Leber Congenital Amaurosis / diagnosis
  • Leber Congenital Amaurosis / genetics
  • Leber Congenital Amaurosis / therapy
  • Male
  • Membrane Proteins / genetics
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Pedigree
  • Retinal Dystrophies* / diagnosis
  • Retinal Dystrophies* / genetics
  • Retinal Dystrophies* / therapy

Substances

  • CRB1 protein, human
  • RDH12 protein, human
  • Alcohol Oxidoreductases
  • Membrane Proteins
  • Eye Proteins
  • Nerve Tissue Proteins

Supplementary concepts

  • Retinal Dystrophy, Early Onset Severe

Grants and funding

The work presented here was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and grants from the Association Retina France and the Foundation JED Belgique to IP.