CCDC151基因新无义变异导致Kartagener综合征伴无精症表型

A Novel Nonsense Mutation in CCDC151 Gene Resulting in Azoospermia Phenotype in Kartagener Syndrome

Kartagener综合征是原发性纤毛运动障碍(primary ciliary dyskinesia, PCD)的一种亚型,是一种罕见先天性的以常染色体隐性遗传为主的疾病,以纤毛运动障碍为特征。为探索1例PCD伴无精子症患者不孕的遗传学病因,同时也为其生殖遗传咨询包括后代发生遗传病的风险提供指导,应用全外显子组测序技术对PCD以及不孕不育相关基因进行生物信息学分析及诊断,发现患者CCDC151基因第8外显子c. 1059C>A (p.Tyr353*)纯合突变可导致PCD 30型。依据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics, ACMG)指南分类,该无义突变为致病性变异。该病患者的相关临床表征有反复发作型中耳炎、慢性支气管炎、鼻塞、纤毛清除缺陷所致呼吸功能不全、哮喘、咳嗽、反复呼吸道感染、鼻息肉、纤毛运动异常、支气管扩张,约50%的患者有完全性内脏反位。目前未见CCDC151基因变异导致男性不育及无精子症表型的报道。本研究发现一个导致PCD的CCDC151基因新突变,丰富了PCD罕见病以及CCDC151基因突变谱,同时首次报道了CCDC151基因突变可导致男性无精子症的不育表型。

Kartagener syndrome, a subtype of primary ciliary dyskinesia(PCD), is a rare congenital disease with an autosomal recessive origin and characterized by ciliary dyskinesia. To explore the genetic etiology of infertility in a case of PCD with azoospermia, and to provide guidance for the patient’s reproductive genetic counseling including the risk of genetic disease in the offspring, bioinformatics analysis and diagnosis of PCD and infertility related genes were performed by using whole exome sequencing technology. The homozygous mutation c. 1059 C>A(p.Tyr353*) in exon 8 of CCDC151 gene was found in the patient, which could lead to ciliary dyskinesia, primary, 30. The nonsense mutation is classified as pathogenic according to the American College of Medical Genetics and Genomics(ACMG) guidelines. The clinical manifestations of this disease include recurrent otitis media, chronic bronchitis, nasal obstruction, respiratory insufficiency due to defective ciliary clearance, asthma, cough, recurrent respiratory tract infection, nasal polyps, abnormal ciliary move-ment, and bronchiectasis, and about 50% of patients have complete visceral reversal. To date, there has been no report of male infertility and azoospermia phenotype caused by CCDC151 gene mutation. Identification of this new CCDC151 mutation causing PCD enriches the spectrum of PCD rare diseases and CCDC151 mutations. It is also the first report on the CCDC151 mutation leading to male azoospermia infertility.