背景:原发性纤毛运动障碍(PCD)是一组由纤毛和鞭毛运动缺陷引起的罕见遗传异质性疾病。PCD患者的临床表型通常包括慢性肺-肺-肺疾病,不孕症,and,在大约一半的案例中,由于左右身体不对称的随机化导致的侧向缺陷。迄今为止,据报道,在这些患者中,有超过50个基因的致病变异,这些基因负责运动性纤毛的结构和组装。虽然已经在来自不同国家的PCD队列中描述了多种群体特异性突变,俄罗斯人口中PCD遗传谱的数据仍然非常有限。
结果:本研究提供了生活在不同国家地区的21个俄罗斯PCD家庭的综合临床和遗传特征。通过高速视频显微镜证实了患者呼吸道上皮细胞纤毛搏动的异常。在大多数情况下,定制设计的小组测序允许发现众所周知或很少提到的PCD相关基因的致病变异,包括DNAH5,DNAH11,CFAP300,LRRC6,ZMYND10,CCDC103,HYDIN,ODAD4、DNAL1和OFD1。变异包括常见的突变,以及新的遗传变异,其中一些可能是俄罗斯患者特有的。对纤毛细胞的mRNA转录本的其他靶向分析使我们能够指定DNAH5中新鉴定的遗传变异体的功能作用(c.20523G>T,c.3599-2A>G),HYDIN(c.10949-2A>G,c.1797C>G),和ZMYND10(c.510+1G>C)关于剪接进程。特别是,剪接位点变异c.2052+3G>T,在四个不相关的家庭中发现,导致DNAH5转录本中外显子14的跳跃,根据受影响先证者的单倍型分析,被提议为Udmurt种群的祖先创始人突变。
结论:报道的数据为俄罗斯人群原发性纤毛运动障碍的遗传背景提供了重要的见解。这些发现清楚地说明了基因组测序与转录分析相结合在新型遗传变体的鉴定和临床解释中的实用性。
BACKGROUND: Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left-right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited.
RESULTS: The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population.
CONCLUSIONS: The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.