Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes

Hum Mutat. 2010 Oct;31(10):E1709-66. doi: 10.1002/humu.21336.

Abstract

Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Vesicular Transport
  • Adolescent
  • Adult
  • Alleles*
  • Antigens, Neoplasm / genetics*
  • Belgium
  • Child
  • Child, Preschool
  • DNA Mutational Analysis / methods
  • Gene Expression Profiling
  • Genetic Testing*
  • Genotype
  • Humans
  • Infant
  • Leber Congenital Amaurosis / diagnosis
  • Leber Congenital Amaurosis / genetics*
  • Leber Congenital Amaurosis / pathology*
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis / methods
  • Phenotype
  • Proteins / genetics
  • Retinal Degeneration / genetics
  • Retinal Dystrophies / genetics
  • Retinal Dystrophies / pathology
  • Young Adult

Substances

  • AHI1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, Neoplasm
  • Cep290 protein, human
  • Neoplasm Proteins
  • Proteins