Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia.
Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia.
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DOI：
10.1534/g3.115.019851
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发表时间：
2015-07-02
期刊：
影响因子：
--
通讯作者：
Kim RH
中科院分区：
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作者：
Marshall CR;Scherer SW;Zariwala MA;Lau L;Paton TA;Stockley T;Jobling RK;Ray PN;Knowles MR;FORGE Canada Consortium;Hall DA;Dell SD;Kim RH
原发性睫状体运动障碍（PCD）是一种常染色体隐性遗传疾病，由于正常的纤毛功能丧失。症状包括新生儿呼吸窘迫、慢性鼻窦炎、支气管扩张、内脏逆位和不孕。临床特征可能是微妙的和高度可变的，使PCD的诊断具有挑战性。诊断可以通过睫状体超微结构分析和/或32个PCD相关基因的分子遗传学检测来证实。然而，由于这种遗传异质性，全面的分子遗传检测不被认为是标准的护理，最有效的分子方法尚未阐明。在这里，我们提出了一种具有成本效益和时间效益的分子遗传算法来解决PCD病例。我们对来自45个临床诊断为PCD的家庭（52例患者）中的20个家庭（22例患者）进行了靶向拷贝数变异（CNV）分析和/或全外显子组测序，这些家庭在对12个PCD相关基因进行桑格测序后没有进行分子遗传学诊断。这种结合的分子遗传学方法导致在最近鉴定的PCD基因中鉴定出20个具有临床显著CNV的家族中的4个（20%）和20个具有双等位基因致病性突变的家族中的7个（35%），导致分子遗传学诊断率增加55%（11/20）。在临床诊断为PCD的患者中，全外显子组测序后进行靶向CNV分析，总体分子遗传产率为76%（34/45）。
Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. Clinical features may be subtle and highly variable, making the diagnosis of PCD challenging. The diagnosis can be confirmed with ciliary ultrastructure analysis and/or molecular genetic testing of 32 PCD-associated genes. However, because of this genetic heterogeneity, comprehensive molecular genetic testing is not considered the standard of care, and the most efficient molecular approach has yet to be elucidated. Here, we propose a cost-effective and time-efficient molecular genetic algorithm to solve cases of PCD. We conducted targeted copy number variation (CNV) analysis and/or whole-exome sequencing on 20 families (22 patients) from a subset of 45 families (52 patients) with a clinical diagnosis of PCD who did not have a molecular genetic diagnosis after Sanger sequencing of 12 PCD-associated genes. This combined molecular genetic approach led to the identification of 4 of 20 (20%) families with clinically significant CNVs and 7 of 20 (35%) families with biallelic pathogenic mutations in recently identified PCD genes, resulting in an increased molecular genetic diagnostic rate of 55% (11/20). In patients with a clinical diagnosis of PCD, whole-exome sequencing followed by targeted CNV analysis results in an overall molecular genetic yield of 76% (34/45).