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Stepwise genetic approach for the diagnosis of primary ciliary dyskinesia in highly consanguineous populations
  1. Dvir Gatt1,2,
  2. Inbal Golan Tripto1,2,
  3. Eran Levanon2,
  4. Noga Arwas1,2,
  5. Guy Hazan1,2,
  6. Soliman Alkrinawi1,
  7. Aviv D Goldbart1,2,
  8. Micha Aviram1,2
  1. 1 Pediatric Pulmonary Unit, Soroka Medical Center, Beer Sheva, Southern, Israel
  2. 2 Ben-Gurion University of the Negev, Beer Sheva, Israel
  1. Correspondence to Dr Dvir Gatt, Soroka Medical Center, Beer Sheva, Southern, Israel; dvirgatt{at}gmail.com

Abstract

Background The American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia (PCD) consider the presence of a bi-allelic pathogenic variant confirmatory for the diagnosis of PCD, with genetic testing recommended when other confirmatory diagnostic tests are less accessible. We present our experience with genetic testing as first line with a proposed algorithm for high consanguinity populations.

Methods Patients with a suspected diagnosis of PCD underwent genetic testing according to a diagnostic algorithm composed of three steps: (1) patients with a previously known causative familial/Bedouin tribal pathogenic variant completed direct testing for a single variant; (2) if the initial test was negative or there was no known pathogenic variant, a PCD genetic panel was completed; (3) if the panel was negative, whole exome sequencing (WES) was completed.

Results Since the implementation of the protocol, diagnosis was confirmed by genetic testing in 21 patients. The majority of them were of Bedouin origin (81%) and had a positive history of consanguinity (65%). Nine patients (43%) had a sibling with a confirmed diagnosis. Most patients (15/21, 71%) were diagnosed by direct pathogenic variant testing and the remainder by genetic panel (19%) and WES (10%). Disease-causing variants were found in nine genes, with DNAL1 (24%) and DNAAF3, DNAAF5, ZMYND10 (14% each) as the most prevalent ones.

Conclusions In highly consanguineous regions, a stepwise genetic testing approach is recommended. This approach may be particularly useful in areas where the ability to obtain confirmatory diagnostic tests through other modalities is less accessible.

  • Paediatrics
  • Respiratory Medicine

Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Footnotes

  • Contributors All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by DG, EL and MA. The first draft of the manuscript was written by DG and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. DG is responsible for the overall content of the work as guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer-reviewed.