Expanding the Spectrum of FOXC1 and PITX2 Mutations and Copy Number Changes in Patients with Anterior Segment Malformations
Expanding the Spectrum of FOXC1 and PITX2 Mutations and Copy Number Changes in Patients with Anterior Segment Malformations
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DOI：
10.1167/iovs.10-5309
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发表时间：
2011-01-01
影响因子：
4.4
通讯作者：
De Baere, Elfride
中科院分区：
文献类型：
--
作者：
D'haene, Barbara;Meire, Francoise;De Baere, Elfride
目的.眼前节发育不全（ASD）包括一组异质性发育异常，影响眼睛眼前节的几个结构。本研究的主要目的是评估80例ASD先证者FOXC 1和PITX 2突变的比例和拷贝数的变化。使用MLPA（多重连接依赖性探针扩增）和直接测序检查患者的FOXC 1和PITX 2拷贝数变化和突变。随后，使用高分辨率微阵列对识别的拷贝数变化进行精细映射。在其余突变阴性的患者中，对FOXC 1和PITX 2 3'非翻译区（UTR）以及其他三个候选基因（P32、PDP 2和FOXC 2）进行测序。13例FOXC 1和8例PITX 2突变，占26%（21/80）的病例。此外，还发现6例FOXC 1和5例PITX 2缺失，解释了14%（11/80）的病例。最小的FOXC 1和PITX 2缺失分别为5.4和1.6 kb。6例携带FOXC 1基因缺失的患者表现出不同的眼外表型特征，如听力障碍（4/6）和智力低下（2/6）。在其余突变阴性患者中未发现进一步的遗传缺陷。FOXC 1和PITX 2基因缺陷解释了我们大型ASD队列的40%。目前的基因内FOXC 1和PITX 2突变谱被大大扩展，已确定的拷贝数变化被精细定位，迄今为止报告的最小FOXC 1和PITX 2缺失被确定，并强调了对FOXC 1和PITX 2基因组景观进行专门拷贝数筛选的必要性。这项研究的独特之处在于在两个基因中同时筛选序列和拷贝数变化。（Invest Ophthalmol维斯科学。2011;52：324-333）DOI：10.1167/iovs.10-5309
PURPOSE. Anterior segment dysgenesis (ASD) comprises a heterogeneous group of developmental abnormalities that affect several structures of the anterior segment of the eye. The main purpose of this study was to assess the proportion of FOXC1 and PITX2 mutations and copy number changes in 80 probands with ASD.METHODS. The patients were examined for FOXC1 and PITX2 copy number changes and mutations using MLPA (multiplex ligation-dependent probe amplification) and direct sequencing. Subsequently, the identified copy number changes were fine-mapped using high-resolution microarrays. In the remaining mutation-negative patients, sequencing of the FOXC1 and-PITX2 3' untranslated regions (UTRs) and three other candidate genes (P32, PDP2, and FOXC2) was performed.RESULTS. Thirteen FOXC1 and eight PITX2 mutations were identified, accounting for 26% (21/80) of the cases. In addition, six FOXC1 and five PITX2 deletions were found, explaining 14% (11/80) of the cases. The smallest FOXC1 and PITX2 deletions were 5.4 and 1.6 kb in size, respectively. Six patients carrying FOXC1 deletions presented with variable extraocular phenotypic features such as hearing defects (in 4/6) and mental retardation (in 2/6). No further genetic defects were found in the remaining mutation-negative patients.CONCLUSIONS. FOXC1 and PITX2 genetic defects explain 40% of our large ASD cohort. The current spectrum of intragenic FOXC1 and PITX2 mutations was extended considerably, the identified copy number changes were fine mapped, the smallest FOXC1 and PITX2 deletions reported so far were identified, and the need for dedicated copy number screening of the FOXC1 and PITX2 genomic landscape was emphasized. This study is unique in that sequence and copy number changes were screened simultaneously in both genes. (Invest Ophthalmol Vis Sci. 2011;52:324-333) DOI:10.1167/iovs.10-5309