Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients

Francesca Boaretto, Deborah Snijders, Cecilia Salvoro, Ambra Spalletta, Maria Luisa Mostacciuolo, Mirella Collura, Salvatore Cazzato, Donata Girosi, Michela Silvestri, Giovanni Arturo Rossi, Angelo Barbato, Giovanni Vazza

Research output: Contribution to journalArticlepeer-review

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic disorder that alters mucociliary clearance, with consequent chronic disease of upper and lower airways. Diagnosis of PCD is challenging, and genetic testing is hampered by the high heterogeneity of the disease, because autosomal recessive causative mutations were found in 34 different genes. In this study, we clinically and molecularly characterized a cohort of 51 Italian patients with clinical signs of PCD. A custom next-generation sequencing panel that enables the affordable and simultaneous screening of 24 PCD genes was developed for genetic analysis. After variant filtering and prioritization, the molecular diagnosis of PCD was achieved in 43% of the patients. Overall, 5 homozygous and 27 compound heterozygous mutations, 21 of which were never reported before, were identified in 11 PCD genes. The DNAH5 and DNAH11 genes were the most common cause of PCD in Italy, but some population specificities were identified. In addition, the number of unsolved cases and the identification of only a single mutation in six patients suggest further genetic heterogeneity and invoke the need of novel strategies to detect unconventional pathogenic DNA variants. Finally, despite the availability of mutation databases and in silico prediction tools helping the interpretation of variants in next-generation sequencing screenings, a comprehensive segregation analysis is required to establish the in trans inheritance and support the pathogenic role of mutations.

Original languageEnglish
Pages (from-to)912-922
Number of pages11
JournalJournal of Molecular Diagnostics
Volume18
Issue number6
DOIs
Publication statusPublished - Nov 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Medicine

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