Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA.
Am J Hum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003. Epub 2012 Dec 20.
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.
原发性纤毛运动障碍（PCD）是一种遗传异质性、常染色体隐性疾病，其特征为耳-鼻-肺疾病和内脏位置异常。14 个基因中的突变可导致 PCD，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 名无关联的纤毛外动力蛋白臂（ODA）缺陷先证者进行了外显子组测序。在一个有两个受影响同胞的家族中，发现了 Chlamydomonas reinhardtii 运动基因 DCC2 的同源物 CCDC114 的突变。对来自 58 个家族的 67 名具有 ODA 缺陷的 PCD 患者进行 Sanger 测序，发现 3 个家族中的 4 名患者存在 CCDC114 突变。所有 6 名 CCDC114 突变患者均具有特征性的耳-鼻-肺疾病，但均无内脏位置异常。在接受外显子组测序的剩余 5 名 PCD 患者中，我们鉴定出了 2 个已知可导致 PCD 的基因（DNAI2、DNAH5）的突变，包括 DNAI2 的一个阿什肯纳兹犹太裔突变。这些结果表明 CCDC114 突变是纤毛运动障碍和 PCD 的原因之一，并进一步证明了外显子组测序在鉴定异质性隐性疾病遗传原因方面的有效性。
