Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. Issue 5 (25th December 2019)

• Record Type: Journal Article
• Authors: Fassad, Mahmoud R.; Patel, Mitali P.; Shoemark, Amelia; Cullup, Thomas; Hayward, Jane; Dixon, Mellisa; Rogers, Andrew V.; Ollosson, Sarah; Jackson, Claire; Goggin, Patricia; Hirst, Robert A.; Rutman, Andrew; Thompson, James; Jenkins, Lucy; Aurora, Paul; Moya, Eduardo; Chetcuti, Philip; O'Callaghan, Chris; Morris-Rosendahl, Deborah J; Watson, Christopher M.; Wilson, Robert; Carr, Siobhan; Walker, Woolf; Pitno, Andreia; Lopes, Susana; Morsy, Heba; Shoman, Walaa; Pereira, Luisa; Constant, Carolina; Loebinger, Michael R.; Chung, Eddie M.K.; Kenia, Priti; Rumman, Nisreen; Fasseeh, Nader; Lucas, Jane S.; Hogg, Claire; Mitchison, Hannah M.;
• Is Part Of: Journal of medical genetics. Volume 57:Issue 5(2020)
• Page Start: 322
• Page End: 330
• Publication Date: 2019-12-25
• Subjects: primary ciliary dyskinesia -- mutation spectrum -- cilia -- bronchiectasis -- population; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2019-106501
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.