Genetic risk estimates for offspring of patients with Stargardt disease

Abstract

BACKGROUND Genetic counseling in autosomal recessive Stargardt disease (STGD1) is complicated because of unknown frequencies of pathogenic ABCA4 alleles across populations, variable and unknown severity of ABCA4 alleles, and incomplete penetrance. METHODS In this cross-sectional study, published ABCA4 variants were categorized by severity based on previous functional and clinical studies and current statistical comparisons of their frequencies in patients versus the general population, their observed versus expected homozygous occurrence in patients, and their occurrence in combination with established mild alleles in patients. The sum allele frequencies of these severity categories were used to estimate inheritance risks for offspring of STGD1 patients and carriers of pathogenic ABCA4 variants. RESULTS The risk for offspring of a STGD1 patient with the severe|severe genotype or a severe|mild with complete penetrance genotype to develop STGD1 at some moment in life was estimated at 2.8-3.1% (1 in 35-32 individuals) and 1.6-1.8% (1 in 62-57 individuals), respectively. The risk to develop STGD1 in childhood was estimated to be 2 to 4-fold lower: 0.7-0.8% (1 in 148-124) and 0.3-0.4% (1 in 295-248), respectively. For offspring of an unaffected ABCA4 variant carrier from a STGD1 family who carries one severe or one mild ABCA4 variant with complete penetrance, the risk to develop STGD1 throughout life is 1.4-1.6% (1 in 71-64) and 0.19-0.21% (1 in 516-487), respectively. CONCLUSION We propose a genotype-based personalized counseling approach to appreciate the large differences in inheritance risk between individuals. We advocate considering the lower risk of early-onset STGD1 compared with the total STGD1 risk.

Quantification of Fundus Autofluorescence Features in a Molecularly Characterized Cohort of More Than 3500 Inherited Retinal Disease Patients from the United Kingdom

“…We also applied AIRDetect to monitor progression in patients belonging to three subgroups of ABCA4 (Figure 6). Patients were classified into three groups (A, B and C) based on increasing severity of genetic variants as defined by Cornelis et al 20,21 . Patients in group A had two severe variants, while group C had a mild variant in trans with any other variant.…”

Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients

“…ABCA4 c.4539 + 2028C > T has a population frequency of 0.00003943 in gnomAD (v3.1) 42 , totaling 6/152,182 alleles. A population frequency of 0.000044 was observed in a recent study of 5579 bi-allelic STGD1 patients 43 . Of the 27 alleles of ABCA4 c.4539 + 2028C > T, 24 of these had the variant ABCA4 c.302 + 68C > T detected concurrently.…”

ABCA4c.859-25A>G, a Frequent Palestinian Founder Mutation Affecting the Intron 7 Branchpoint, Is Associated With Early-Onset Stargardt Disease

“… 1 It is caused by biallelic variants in the gene encoding the transmembrane ATP-binding cassette transporter type A4 (ABCA4). 2 More than 2200 unique variants have been reported for ABCA4 ( http://www.lovd.nl/ABCA4 ), 3 , 4 which have been linked to a spectrum of autosomal recessive maculopathies, such as classical STGD1, fundus flavimaculatus, cone-rod dystrophy (CRD), and atypical retinitis pigmentosa (RP). 2 , 5 – 8 …”