Whole Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia
Christian R. Marshall1, Stephen W. Scherer2, Maimoona A. Zariwala3, Lynette Lau1, Tara A. Paton1, Tracy Stockley1, Rebekah K. Jobling1, Peter N. Ray1, Michael R. Knowles3, David A. Hall4, Sharon D. Dell2 and Raymond H. Kim
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, due to this genetic heterogeneity, comprehensive molecular genetic testing is not considered 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 in solving PCD cases. We conducted targeted copy number variation (CNV) analysis and/or whole exome sequencing (WES) 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 4/20 (20%) families with clinically significant CNVs and 7/20 (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, WES before targeted CNV analysis results in an overall molecular genetic yield of 76% (34/45).
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