Abstract
BackgroundMore than 1500 variants in the ATP-binding cassette, sub-family A, member 4 (ABCA4), locus underlie a heterogeneous spectrum of retinal disorders ranging from aggressive childhood-onset chorioretinopathy to milder late-onset macular disease. Genotype-phenotype correlation studies have been limited in clinical applicability as patient cohorts are typically small and seldom capture the full natural history of individual genotypes. To overcome these limitations, we constructed a genotype-phenotype correlation matrix that provides quantifiable probabilities of long-term disease outcomes associated with specific ABCA4 genotypes from a large, age-restricted patient cohort.MethodsThe study included 112 unrelated patients at least 50 years of age in whom 2 pathogenic variants were identified after sequencing of the ABCA4 locus. Clinical characterization was performed using the results of best corrected visual acuity, retinal imaging, and full-field electroretinogram testing.ResultsFour distinct prognostic groups were defined according to the spatial severity of disease features across the fundus. Recurring genotypes were observed in milder prognoses, including a newly defined class of rare hypomorphic alleles. PVS1 (predicted null) variants were enriched in the most severe prognoses; however, missense variants were present in a larger-than-expected fraction of these patients. Analysis of allele combinations and their respective prognostic severity showed that certain variants, such as p.(Gly1961Glu), and both rare and frequent hypomorphic alleles, were “clinically dominant” with respect to patient phenotypes irrespective of the allele in trans.ConclusionThese results provide much-needed structure to the complex genetic and clinical landscape of ABCA4 disease and add a tool to the clinical repertoire to quantitatively assess individual genotype-specific prognoses in patients.FUNDINGNational Eye Institute, NIH, grants R01 EY028203, R01 EY028954, R01 EY029315, P30 19007 (Core Grant for Vision Research); the Foundation Fighting Blindness USA, grant no. PPA-1218-0751-COLU; and Research to Prevent Blindness.
Highlights
These results provide much-needed structure to the complex genetic and clinical landscape of ABCA4 disease and add a tool to the clinical repertoire to quantitatively assess individual genotype-specific prognoses in patients
Pathogenic variants in the ATP-binding cassette, sub-family A, member 4 (ABCA4), gene are the underlying molecular cause of a large and complex group of autosomal-recessive retinal degenerative disorders characterized by progressive loss of central vision [1]
Consistent with the model that clinical phenotypes are dependent on the residual activity of ABCA4 protein [5, 6], variants resulting in null alleles, such as stop-gain, frameshift, canonical splice site, and large copy number variants, have been documented in the most severe phenotypes, such as cone-rod dystrophy, rapid-onset chorioretinopathy (ROC), and even generalized choriocapillaris dystrophies with retinitis pigmentosa–like features [6–10]
Summary
Pathogenic variants in the ATP-binding cassette, sub-family A, member 4 (ABCA4), gene are the underlying molecular cause of a large and complex group of autosomal-recessive retinal degenerative disorders characterized by progressive loss of central vision [1]. 2); advances in genetic screening capabilities, aided by high-resolution diagnostic imaging technology, have broadened the phenotypic profile of ABCA4 disease to an expansive clinical spectrum encompassing severe adolescent-onset to mild late-onset retinal disorders [3] This phenotypic heterogeneity is matched by an extensive array of pathogenic variations across the approximately 140 kb–spanning ABCA4 locus (1p22.1). Despite being highly prevalent in patients, the disease penetrance of this allele has been disputed as its frequency in the general population is relatively high (minor allele frequency [MAF] ≈ 0.5% in Europeans) and in certain ethnic groups is much higher [13, 14] We recently resolved this controversy, for the most part, by showing that the contribution of an additional deep intronic variant, c.769-784C>T [15, 16], present in cis, is required for clinical penetrance, in homozygotes [17]. We constructed a genotype-phenotype correlation matrix that provides quantifiable probabilities of long-term disease outcomes associated with specific ABCA4 genotypes from a large, age-restricted patient cohort
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