Heterozygous Deep-Intronic Variants and Deletions in ABCA4 in Persons with Retinal Dystrophies and One Exonic ABCA4 Variant
Heterozygous Deep-Intronic Variants and Deletions in ABCA4 in Persons with Retinal Dystrophies and One Exonic ABCA4 Variant
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DOI：
10.1002/humu.22717
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发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Cremers, Frans P. M.
中科院分区：
文献类型：
--
作者：
Bax, Nathalie M.;Sangermano, Riccardo;Cremers, Frans P. M.
ABCA4基因变异导致常染色体隐性遗传性Stargardt病和视锥-视杆细胞营养不良。此前对ABCA4外显子的序列分析显示，在45个先证者中，每个人都有一个致病变异。为了确定这些病例中缺失的变异体，我们对ABCA4进行了基于多重连接依赖的探针扩增的缺失扫描。此外，我们还对启动子区域、包含5个深内含子剪接变异体的片段和包含弱剪接位点的15个深内含子区域进行了测序。在2个先证者中发现ABCA4外显子5或外显子20~22的杂合性缺失，在6个先证者中发现深内含子杂合变异，在1个先证者中发现1个深内含子变异并伴有外显子20~22的缺失。根据眼科发现和已鉴定的反式外显子变异的特征，深内含子变异V1和V4分别被预测为相对较轻和较严重。这些发现对于适当的遗传咨询和针对变异的特定疗法的开发是重要的。
Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of ABCA4 exons previously revealed one causative variant in each of 45 probands. To identify the missing variants in these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning of ABCA4. In addition, we sequenced the promoter region, fragments containing five deep-intronic splice variants, and 15 deep-intronic regions containing weak splice sites. Heterozygous deletions spanning ABCA4 exon 5 or exons 20-22 were found in two probands, heterozygous deep-intronic variants were identified in six probands, and a deep-intronic variant was found together with an exon 20-22 deletion in one proband. Based on ophthalmologic findings and characteristics of the identified exonic variants present in trans, the deep-intronic variants V1 and V4 were predicted to be relatively mild and severe, respectively. These findings are important for proper genetic counseling and for the development of variant-specific therapies.