Exome Sequencing Identifies Mutations in CCDC114 as a Cause of Primary Ciliary Dyskinesia
Exome Sequencing Identifies Mutations in CCDC114 as a Cause of Primary Ciliary Dyskinesia
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DOI：
10.1016/j.ajhg.2012.11.003
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发表时间：
2013-01-10
影响因子：
9.8
通讯作者：
Zariwala, Maimoona A.
中科院分区：
文献类型：
--
作者：
Knowles, Michael R.;Leigh, Margaret W.;Zariwala, Maimoona A.
原发性纤毛运动障碍（PCD）是一种遗传异质性常染色体隐性遗传疾病，以耳鼻喉科疾病和位置异常为特征。已经在14个基因中鉴定出导致PCD的突变，但它们总共仅占所有PCD的约60%。为了鉴定导致PCD的突变，我们对6个睫状体外动力蛋白臂（ODA）缺陷的无关先证者进行了外显子组测序。在一个有两个受影响的兄弟姐妹的家庭中发现了CCDC114突变，CCDC114是莱茵衣藻运动基因DCC 2的直系同源物。对来自58个家庭的另外67名患有ODA缺陷的PCD个体进行的桑格测序显示，3个家庭的4名个体存在CCDC 114突变。所有6个CCDC114突变的个体都有特征性的耳鼻肺疾病，但没有一个有位置异常。在剩下的5名接受外显子组测序的PCD患者中，我们确定了已知引起PCD的两个基因（DNAI2，DNAH5）的突变，包括DNAI2中的德系犹太创始人突变。这些结果揭示了CCDC114中的突变是纤毛运动障碍和PCD的原因，并进一步证明了外显子组测序在鉴定异质性隐性疾病的遗传原因中的实用性。
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 14 genes, but they collectively account for only -60% of all PCD. To identify mutations that cause PCD, we performed exome sequencing on six unrelated probands with ciliary outer dynein arm (ODA) defects. Mutations in CCDC114, an ortholog of the Chlamydomonas reinhardtii motility gene DCC2, were identified in a family with two affected siblings. Sanger sequencing of 67 additional individuals with PCD with ODA defects from 58 families revealed CCDC114 mutations in 4 individuals in 3 families. All 6 individuals with CCDC114 mutations had characteristic oto-sino-pulmonary disease, but none had situs abnormalities. In the remaining 5 individuals with PCD who underwent exome sequencing, we identified mutations in two genes (DNAI2, DNAH5) known to cause PCD, including an Ashkenazi Jewish founder mutation in DNAI2. These results revealed that mutations in CCDC114 are a cause of ciliary dysmotility and PCD and further demonstrate the utility of exome sequencing to identify genetic causes in heterogeneous recessive disorders.