Association Between Genotype and Phenotype Severity in ABCA4-Associated Retinopathy

Abstract

ImportanceABCA4-associated retinopathy is a common inherited retinal disease, and its phenotype spans from late-onset macular dystrophy to extensive cone-rod degeneration. Over 2000 disease-causing variants in the ABCA4 gene have been identified.ObjectiveTo investigate genotype-phenotype correlations in ABCA4-associated retinopathy.Design, Setting, and ParticipantsThis cohort study took place at a single referral center for inherited retinal diseases in Italy. Data were prospectively acquired from January 2015 to June 2022. Patients diagnosed with an inherited retinal disease related to biallelic ABCA4 variants were included for analysis.ExposureGenotype, classified into 4 groups according to the presence of the (1) p.Gly1961Glu allele, (2) a hypomorphic allele, (3) at least 1 moderate variant (moderate genotypes), or (4) 2 biallelic severe variants (severe genotypes).Main Outcomes and MeasuresTotal decreased autofluorescence (TDAF) and definitely decreased autofluorescence (DDAF) areas, inner and outer retinal volumes, and the respective progression rate.ResultsA total of 71 patients (median [IQR] age, 34 [22.4-47.2] years; 40 [56%] female) were included in the study, and 54 (76%) were followed up for a median (IQR) of 3.5 (1.6-4.7) years. Compared with moderate genotypes, those with the p.Gly1961Glu allele had smaller TDAF lesions by 61% (95% CI, −78% to −33%; P < .001) and DDAF lesions by 77% (95% CI, −93% to −18%; P = .02), along with slower growth rates for both TDAF (0.05 mm/y; 95% CI, 0.01-0.07; P < .001) and DDAF (0.06 mm/y; 95% CI, 0-0.12; P = .004). Hypomorphic alleles were associated with a thicker inner (+0.19 mm3; 95% CI, +0.02 to +0.36; P = .03) and outer retinal volume (+0.16 mm3; 95% CI, +0.03 to +0.28; P = .01) compared with moderate genotypes as well as a slower TDAF growth rate (0.05 mm/y; 95% CI, 0.01-0.08; P = .007). Severe genotypes had a 7-fold larger TDAF area (95% CI, 3.4-14.7; P < .001) and 11-fold larger DDAF area (95% CI, 2.9-42.1; P < .001) compared with moderate genotypes, along with faster growth rates estimated at 0.16 mm/y for TDAF (95% CI, 0.12-0.20; P < .001) and 0.17 mm/y for DDAF (95% CI, 0.12-0.23; P < .001).Conclusions and RelevanceIn this study of ABCA4-associated retinopathy, a 4-tier classification of genotypes was found to capture substantial variation in disease phenotype severity. These findings could prove beneficial for the prognostication of patients and warrant consideration of genotype in the design of future clinical trials.

ABCA4-related retinopathies in Lebanon

“…Other aspects of IRDs that appear with central vision loss include macular dystrophies (MD) that affect mainly the macula [ 3 , 7 ]. With an incidence rate of 1 in 8,000–10,000 individuals, Stargardt disease (STGD; MIM 248200 ) emerges as the prevailing aspect of MD with an autosomal recessive mode of inheritance affiliated with etiological variants in the ATP-binding cassette transporter type A4 ( ABCA4 ) [ 8 , 9 ].…”

“…The ABCA4 gene, initially identified by Allikmets and colleagues in 1997 as the causative gene for STGD [ 10 ], was later found to be associated with some forms of RCD and CRD, depending on the ABCA4 variant type and the residual protein activity [ 11 ]. ABCA4 is a 50 exons' locus on the short arm of chromosome 1 (1p21–p22.1) that encodes a single-chain ATP-binding cassette transporter protein situated at the outer segments of rod and cone photoreceptors [ 8 , 9 ]. ABCA4 protein moves all trans -retinal and toxic substances from the disc lumen to the photoreceptors' cytoplasm.…”

Deciphering complexity: TULP1 variants linked to an atypical retinal dystrophy phenotype

“…The identification of over 300 genes conclusively linked to IRDs (RetNet, https://web.sph.uth.edu/RetNet/ ; accessed on 13 January 2024) also exhibits the complex nature of these conditions, marked by extensive genetic heterogeneity and variable expressivity. Notably, different variants within the same gene can lead to a wide range of clinical presentations ( Chen et al, 2018 ; Bianco et al, 2023 ), and conversely, similar clinical manifestations may result from variants in different genes ( García Bohórquez et al, 2021 ; Perea-Romero et al, 2021 ; Smirnov et al, 2021 ). Additionally, evidence supports the significant role of gene modifiers in human eye diseases ( Meyer and Anderson, 2017 ; Li et al, 2021 ), introducing an added layer of complexity to the diagnosis and understanding of IRDs.…”