Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort

Mahmoud R. Fassad, Mitali P. Patel, Amelia Shoemark, Thomas Cullup, Jane Hayward, Mellisa Dixon, Andrew V. Rogers, Sarah Ollosson, Claire Jackson, Patricia Goggin, Robert A. Hirst, Andrew Rutman, James Thompson, Lucy Jenkins, Paul Aurora, Eduardo Moya, Philip Chetcuti, Chris O'Callaghan, Deborah J. Morris-Rosendahl, Christopher M. WatsonRobert Wilson, Siobhan Carr, Woolf Walker, Andreia Pitno, Susana Lopes, Heba Morsy, Walaa Shoman, Luisa Pereira, Carolina Constant, Michael R. Loebinger, Eddie M. K. Chung, Priti Kenia, Nisreen Rumman, Nader Fasseeh, Jane S. Lucas, Claire Hogg, Hannah M. Mitchison (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)
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Background: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.

Methods: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.

Results: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results.

Conclusions: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

Original languageEnglish
Pages (from-to)322-330
Number of pages9
JournalJournal of Medical Genetics
Issue number5
Early online date25 Dec 2019
Publication statusPublished - 23 Apr 2020


  • bronchiectasis
  • cilia
  • mutation spectrum
  • population
  • primary ciliary dyskinesia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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