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.
IMPORTANCE A new statistical approach is needed to describe the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene. OBJECTIVES To describe the primary phenotypic characteristics and differences between type I and type II Usher syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ 2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss. RESULTS The comparison between patients with type I Usher syndrome and those with type II Usher syndrome revealed P < .001 for most items analyzed. The most frequent mutations in the USH2A gene were the p.Glu767Serfs*21 and p.Cys759Phe mutations, with an allelic frequency of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. The phenotypic analysis for patients carrying p.Cys759Phe showed P < .001 for most items analyzed when compared with patients carrying p.Glu767Serfs*21 and when compared with patients carrying other mutations in the USH2A gene. None of the p.Cys759Phe patients exhibited a severe hearing loss phenotype, and more than 60% had only mild hearing loss. Most patients carrying the p.Glu767Serfs*21 mutation (72.1%) were moderately deaf. CONCLUSIONS AND RELEVANCE Our study presents the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene. Detailed genotype-phenotype correlations, as presented in our study, allow for a better correlation of clinical signs with a known genotype and can improve the clinical management, genetic counseling, and risk assessment of patients with Usher syndrome because an estimated prognosis of their disease can be made.
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