Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.
Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.
复制标题
常染色体隐性性视网膜营养不良中与ABCA4疾病相关等位基因的结果：420个西班牙家庭的回顾性分析。
DOI：
10.1016/j.ophtha.2013.04.002
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发表时间：
2013-11
期刊：
影响因子：
13.7
通讯作者：
Ayuso C
中科院分区：
文献类型：
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作者：
Riveiro-Alvarez R;Lopez-Martinez MA;Zernant J;Aguirre-Lamban J;Cantalapiedra D;Avila-Fernandez A;Gimenez A;Lopez-Molina MI;Garcia-Sandoval B;Blanco-Kelly F;Corton M;Tatu S;Fernandez-San Jose P;Trujillo-Tiebas MJ;Ramos C;Allikmets R;Ayuso C
对常染色体隐性视网膜疾病（包括Stargardt病（arSTGD）、锥杆营养不良（arCRD）和色素性视网膜炎（arRP））的西班牙家族中所有检测到的ABCA4基因突变进行全面概述。此外，通过考虑变异类型和发病年龄，评估基因型-表型相关性和10年内疾病进展。系列。共有420个无血缘关系的西班牙家庭：259个arSTGD， 86个arCRD和75个arRP。通过ABCR400基因分型芯片、变性高效液相色谱（dHPLC）和高分辨率熔融（HRM）扫描对西班牙家族进行分析。使用直接测序作为鉴定变异的确认技术。通过多重结扎探针分析（MLPA）筛选ABCA4基因，以检测可能的大缺失或插入。选择的家族进一步通过下一代测序（NGS）进行分析。DNA序列变异，突变检出率，单倍型，发病年龄，中央或周围视力丧失，夜盲症。总体而言，我们在arSTGD和arCRD患者队列中分别检测到70.5%和36.6%的预期ABCA4突变。在ABCA4基因完全测序的队列中，STGD的检出率为73.6%，CRD的检出率为66.7%。然而，arRP家族中可能致病的ABCA4等位基因的频率仅略高于普通人群。此外，在一些家族中，其他已知arRP基因的突变与疾病表型分离。对arSTGD和arCRD中ABCA4等位基因的日益了解有助于疾病的诊断和预后，并且在为治疗干预的新兴临床试验选择患者时也至关重要。随着abca4相关疾病的发展，视网膜营养不良的发病年龄评估，准确的临床诊断和基因检测是至关重要的。我们认为ABCA4突变可能与rp样表型相关，通常是严重（零）突变和/或长期晚期疾病的结果。具有“经典”arRP表型的患者，特别是从发病开始，应该首先筛查已知arRP基因的突变，而不是ABCA4。
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. Case series. A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD and 75 arRP. 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). DNA sequence variants, mutation detection rates, haplotypes, age of onset, central or peripheral vision loss, night blindness. 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. 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.