A Method for Deducing the Pathogenic Contribution of Individual Recessive Disease Alleles

Abstract

Purpose: : Accurate prediction of the pathogenic effects of specific genotypes is useful for a variety of purposes ranging from genetic counseling to the design and execution of clinical trials. However, for recessive diseases in outbred populations it can be difficult to deduce the relative pathogenic contribution of individual alleles because relatively few affected individuals share the same two disease-causing alleles.

Methods: : An inexpensive high-throughput allele-specific assay was designed for the detection of 24 of the most common disease-causing alleles in the ABCA4 gene. This assay was used to screen 351 patients with the clinical features of Stargardt disease, 238 with cone-rod dystrophy, 237 with retinitis pigmentosa and 253 controls.

Results: : The assay used in this study succeeded in detecting at least one disease-causing allele in 50% of patients affected with Stargardt disease, 25% affected with cone-rod dystrophy and 12% affected with RP. The five most common disease-causing ABCA4 alleles were each observed in more than 25 affected individuals (range 25-48) in the study. Since these five groups of patients each share one disease allele, the genetic contribution to the phenotypic differences observed within each group could be ascribed to the second disease allele. Sequential analysis of these five groups allowed the relative pathogenicity of fifteen ABCA4 alleles to be determined. Two of the most common disease-causing alleles (G1961E and G863A) were also found to be the least pathogenic. These alleles rarely cause disease in the homozygous state or in the compound heterozygous state with each other. The four most virulent alleles (R152X, C1490Y, C1488R, and IVS14-1 G>A) were each found more commonly in cone-rod dystrophy or RP patients than in patients with Stargardt disease.

Conclusions: : The availability of inexpensive, high-throughput assays for known disease-causing alleles makes it possible to identify relatively large numbers of patients that harbor at least one copy of the more common alleles. The differences in disease severity among the members of such a group can then be assigned, at least in relative terms, to the second allele.

Keywords: genetics • retinal degenerations: hereditary