Outcome of ABCA4 Disease-Associated Alleles in Autosomal Recessive Retinal Dystrophies

Abstract

Objective To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP). Also, to assess genotype-phenotype correlation and disease progression in 10 years by considering type of variants and age of onset. Design Case series. Participants A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD and 75 arRP. Methods Spanish families were analysed through a combination of ABCR400 genotyping microarray, denaturing High-Performance Liquid Chromatography (dHPLC) and High Resolution Melting (HRM) scanning. Direct sequencing was used as confirmation technique for the identified variants. Screening by Multiple Ligation Probe Analysis (MLPA) was used in order to detect possible large deletions or insertions in the ABCA4 gene. Selected families were further analysed by Next Generation Sequencing (NGS). Main Outcome Measures DNA sequence variants, mutation detection rates, haplotypes, age of onset, central or peripheral vision loss, night blindness. Results Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was completely sequenced the detection rates reached 73.6% for STGD and 66.7% for CRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher to that in the general population. Moreover, in some families mutations in other known arRP genes segregated with the disease phenotype. Conclusions An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and is also paramount in selecting patients for emerging clinical trials of therapeutic interventions. As ABCA4-associated diseases are evolving retinal dystrophies, assessment of age of onset, accurate clinical diagnosis and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with an RP-like phenotype often as a consequence of severe (null) mutations and/or in cases of long-term, advanced disease. Patients with “classical” arRP phenotypes, especially from the onset of the disease, should be first screened for mutations in known arRP genes and not ABCA4.

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses

“…Mutations in known genes are estimated to contribute to IRD pathology in about 50% of dominant cases (Daiger, 2004). Whereas, in recessive conditions, mutations in known genes contribute to 40-50% of cases (Riveiro-Alvarez et al, 2013). The rate of detection of causative mutations in our study conducted between 2009 and 2011 is consistent with earlier reported findings.…”

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases

“…At present, a clear correlation between ABCA4 genotype and retinal phenotypes has not been well established, [42][43][44][45][46] and only one model based on a paper from Maugeri et al 47 has been proposed. Some authors report higher frequency of severe retinal phenotypes in patients carrying null ABCA4 variants, 48,49 and some specific genotypes have been associated with peculiar clinical features. 50 Despite substantial progress in determining the causal genetic variations, some ambiguities are still present because in clinically confirmed ABCA4 disease no mutations are found, suggesting that a significant revision of diagnostic screening and assessment of ABCA4 variations is needed in retinal diseases etiology.…”

A Cost-Effective Mutation Screening Strategy for Inherited Retinal Dystrophies

“…For those cases that skipped our screening strategy, a second analysis based on a more specific strategy can be considered, such as disease-specific arrays (Asper custom-designed arrays), NGS-based methods or multiplex ligation-dependent probe amplification for some of the genes with a high prevalence of cases reported with genomic rearrangements [17,18,19,20,34,35,36,37,38,39,40,41,42,43]. Thus, our strategy or the combined use of our approach with a more specific (and expensive) one could result in a useful fast and cost-effective strategy for diagnostic purposes in cases of IRD.…”