Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Am J Ophthalmol. 2020 Nov;219:195-204. doi: 10.1016/j.ajo.2020.06.027. Epub 2020 Jun 30.


Purpose: To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD).

Design: Cohort study.

Methods: We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies. Medical history and ophthalmologic data were obtained from 372 patients. Genotype-phenotype correlation studies were carried out for the following variables: variant type, age at symptom onset (AO), and clinical phenotype.

Results: A total of 228 different pathogenic variants were identified in 506 ABCA4 patients, 50 of which were novel. Genotype-phenotype correlations showed that most of the patients with biallelic truncating variants presented with CRD and that these cases had a significantly earlier AO than patients with STGD1. Three missense variants are associated with CRD for the first time (c.1804C>T; p.[Arg602Trp], c.3056C>T; p.[Thr1019Met], and c.6320G>C; p.[Arg2107Pro]). Analysis of the most prevalent ABCA4 variant in Spain, c.3386G>T; p.(Arg1129Leu), revealed that is correlated to STGD1, later AO, and foveal sparing.

Conclusions: Our study, conducted in the largest ABCA4-associated disease cohort reported to date, updates the genotype-phenotype model established for ABCA4 variants and broadens the mutational spectrum of the gene. According to our observations, patients with ABCA4 presenting with 2 truncating variants may first present features of STGD1 but eventually develop rod dysfunction, and specific missense variants may be associated with a different phenotype, underscoring the importance of an accurate genetic diagnosis. Also, it is a prerequisite for enrollment in clinical trials, and to date, no other treatment has been approved for STGD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Adult
  • Age of Onset
  • Alleles
  • Cohort Studies
  • Cone-Rod Dystrophies / diagnosis
  • Cone-Rod Dystrophies / genetics*
  • Electroretinography
  • Female
  • Genetic Association Studies
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Microsatellite Repeats / genetics
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics
  • Spain
  • Stargardt Disease / diagnosis
  • Stargardt Disease / genetics*
  • Tomography, Optical Coherence
  • Visual Acuity / physiology
  • Young Adult


  • ABCA4 protein, human
  • ATP-Binding Cassette Transporters