Dominant optic atrophy in Denmark - report of 15 novel mutations in OPA1, using a strategy with a detection rate of 90%.
Dominant optic atrophy in Denmark - report of 15 novel mutations in OPA1, using a strategy with a detection rate of 90%.
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DOI：
10.1186/1471-2350-13-65
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发表时间：
2012-08-02
影响因子：
--
通讯作者：
Grønskov K
中科院分区：
文献类型：
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作者：
Almind GJ;Ek J;Rosenberg T;Eiberg H;Larsen M;Lucamp L;Brøndum-Nielsen K;Grønskov K
丹麦常染色体显性遗传性视神经萎缩患者OPA1基因突变谱的研究对93个无亲缘关系的ADOA家系的索引患者进行了OPA1中常见的丹麦创始人突变(c.2826_2836缺失GGATGCTCCA)的评估。如果为阴性，则进行编码序列的直接DNA测序和多重连接依赖探针扩增(MLPA)。此前曾报道过MLPA分析的结果。进行单倍型分析，分析单核苷酸多态性(SNP)。回顾性临床资料从医疗档案中检索。93个家系中可能有84个(90%)发现致病突变，其中包括15个新突变。3个突变c.983A >； G、c.2708_2711delTTAG和c.2826_2836缺失GGATGCTCCA分别导致10、11和28个家系的ADOA，分别占11%、12%和30%。在十个C.983A >； G家族中，有九个家庭的常见单倍型表明他们是单一创始人的后代。C.2708_2711delTTAG突变至少存在于两种单倍型上，并在不同种族中反复报道，是一个突变热点。具有后两个突变的索引患者的临床检查显示明显的家族间和家族内变异。OPA1基因突变检测有助于诊断。我们已经在90%的家系中发现了OPA1的突变，其中包括15个新的突变。DNA测序和MLPA分析都是获得高检测率所必需的。在丹麦，超过一半的受影响家庭由三种常见的突变所代表，其中至少两种是由于创始人效应，这可能是丹麦ADOA高发的原因。
Investigation of the OPA1 mutation spectrum in autosomal dominant optic atrophy (ADOA) in Denmark. Index patients from 93 unrelated ADOA families were assessed for a common Danish founder mutation (c.2826_2836delinsGGATGCTCCA) inOPA1. If negative, direct DNA sequencing of the coding sequence and multiplex ligation-dependent probe amplification (MLPA) were performed. Results from MLPA analysis have been previously reported. Haplotype analysis was carried out analysing single nucleotide polymorphisms (SNP). Retrospective clinical data were retrieved from medical files. Probably causative mutations were identified in 84 out of 93 families (90%) including 15 novel mutations. Three mutations c.983A > G, c.2708_2711delTTAG and c.2826_2836delinsGGATGCTCCA, were responsible for ADOA in10, 11 and 28 families, respectively, corresponding to 11%, 12% and 30%. A common haplotype in nine of ten c.983A > G families suggests that they descend from a single founder. The c.2708_2711delTTAG mutation was present on at least two haplotypes and has been repeatedly reported in various ethnic groups,thus represents a mutational hotspot. Clinical examinations of index patients with the two latter mutations demonstrated large inter- and intra-familial variations apparently. Genetic testing for OPA1mutations assist in the diagnosis. We have identified mutations in OPA1 in 90% of families including 15 novel mutations. Both DNA sequencing and MLPA analysis are necessary to achieve a high detection rate. More than half of the affected families in Denmark are represented by three common mutations, at least two of which are due to a founder effect, which may account for the high prevalence of ADOA in Denmark.