Kartagener综合征中新等位基因的发现

文献信息

中文摘要

背景： Kartagener综合征（KS）是一种罕见的、通常为常染色体隐性的纤毛病，是原发性纤毛运动障碍（PCD）的一个亚型，以内脏反位、支气管扩张和慢性鼻窦炎为特征。KS约占PCD病例的50%，由运动纤毛功能受损所致。胚胎期节点纤毛摆动缺陷导致左右轴决定呈随机性并出现内脏位置异常。尽管已发现众多基因与PCD相关，但高达30%的病例在遗传学上仍未明确，且专门针对KS队列的研究仍然有限。方法：本研究对来自一个土耳其KS队列的17例成年患者进行全外显子组测序，以鉴定致病变异和新的候选基因。变异依据测序质量、人群等位基因频率和预测的功能影响进行优先级排序，包括单核苷酸变异、小插入/缺失和拷贝数变异。将队列限定为内脏反位个体，为变异解读提供了表型特异性的背景，因为通常与左右轴决定无关的基因在本研究人群中不太可能解释疾病。结果：在多个已知PCD基因中鉴定出致病性或可能疾病相关变异，包括DNAH5、DNAI1、DNAI2、DNAAF1、DNAAF3、CFAP300和ODAD1，并检测到若干新等位基因。在一例缺乏已知PCD基因双等位基因变异的患者中，扩展分析发现纤毛相关基因DLEC1和DNAAF9的杂合变异，以及EZR（一个已知影响运动纤毛功能的基因）的半合子拷贝数缺失。这些并存发现的可能相关性值得在遗传学未明确的病例中进一步研究。结论：总体而言，对该KS特异性队列的分析显示出较高的诊断率，扩展了与Kartagener综合征相关的变异谱，并进一步支持了表型驱动的基因组分析在遗传异质性纤毛病中的实用性。

英文摘要

Kartagener's syndrome (KS) is a rare, typically autosomal recessive ciliopathy and a subtype of primary ciliary dyskinesia (PCD), characterized by situs inversus, bronchiectasis, and chronic sinusitis. KS accounts for approximately 50% of PCD cases and results from impaired motile cilia function. Defective embryonic nodal ciliary beating leads to stochastic left-right axis determination and situs abnormalities. Although numerous genes have been implicated in PCD, up to 30% of cases remain genetically unresolved, and studies specifically focused on KS cohorts remain limited. Here, we performed whole exome sequencing in 17 adult patients from a Turkish KS cohort to identify pathogenic variants and novel candidate genes. Variants were prioritised based on sequencing quality, population allele frequency, and predicted functional impact, and included single-nucleotide variants, small insertions/deletions, and copy-number variations. The restriction of the cohort to individuals with situs inversus provided a phenotype-specific context for variant interpretation, as genes not typically associated with left-right axis determination were less likely to account for disease in this study population. Pathogenic or potentially disease-associated variants were identified in multiple established PCD genes, including DNAH5, DNAI1, DNAI2, DNAAF1, DNAAF3, CFAP300, and ODAD1, with several novel alleles detected. In one patient lacking biallelic variants in known PCD genes, expanded analysis identified heterozygous variants in the cilia-associated genes DLEC1 and DNAAF9 together with a hemizygous copy number loss in EZR, a gene known to affect motile cilia function. The possible relevance of these concurrent findings warrants further investigation in genetically unresolved cases. Overall, analysis of this KS-specific cohort demonstrated a high diagnostic yield, expanded the variant spectrum associated with Kartagener's syndrome, and further supported the utility of phenotype-driven genomic analysis in genetically heterogeneous ciliopathies.