Shenzhen Institute of Respiratory Disease, The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, China.
Clinical Centre, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, China.
Am J Med Genet A. 2022 Oct;188(10):3024-3031. doi: 10.1002/ajmg.a.62912. Epub 2022 Jul 23.
The genetic factors contributing to primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder, remain elusive for ~20%-35% of patients with complex and abnormal clinical phenotypes. Our study aimed to identify causative variants of PCD-associated pathogenic candidate genes using whole-exome sequencing (WES). All patients were diagnosed with PCD based on clinical phenotype or transmission electron microscopy images of cilia. WES and bioinformatic analysis were then conducted on patients with PCD. Identified candidate variants were validated by Sanger sequencing. Pathogenicity of candidate variants was then evaluated using in silico software and the American College of Medical Genetics and Genomics (ACMG) database. In total, 13 rare variants were identified in patients with PCD, among which were three homozygous causative variants (including one splicing variant) in the PCD-associated genes CCDC40 and DNAI1. Moreover, two stop-gain heterozygous variants of DNAAF3 and DNAH1 were classified as pathogenic variants based on the ACMG criteria. This study identified novel potential pathogenic genetic factors associated with PCD. Noteworthy, the patients with PCD carried multiple rare causative gene variants, thereby suggesting that known causative genes along with other functional genes should be considered for such heterogeneous genetic disorders.
导致原发性纤毛运动障碍（PCD）的遗传因素仍然难以确定，这种疾病是一种罕见的常染色体隐性遗传病，约有 20%-35%的具有复杂和异常临床表型的患者存在这种情况。我们的研究旨在使用全外显子组测序（WES）鉴定与 PCD 相关的致病性候选基因的致病变异。所有患者均根据临床表型或纤毛的透射电子显微镜图像诊断为 PCD。然后对 PCD 患者进行 WES 和生物信息学分析。通过 Sanger 测序验证候选变异。然后使用计算机软件和美国医学遗传学与基因组学学院（ACMG）数据库评估候选变异的致病性。总共在 PCD 患者中发现了 13 个罕见变异，其中包括 PCD 相关基因 CCDC40 和 DNAI1 中的三个纯合致病变异（包括一个剪接变异）。此外，根据 ACMG 标准，DNAAF3 和 DNAH1 的两个移码杂合变异被归类为致病性变异。本研究确定了与 PCD 相关的新的潜在致病遗传因素。值得注意的是，PCD 患者携带多个罕见的致病基因变异，这表明对于这种异质性遗传疾病，应该考虑已知的致病基因以及其他功能基因。
