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

• Published in: Journal of medical genetics Vol. 57; no. 5; pp. 322 - 330
• Main 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.
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2020
• Subjects: Alleles; Cilia; Defects; Diagnosis; Dyskinesia; Evolution; Families & family life; Genes; Genetic screening; Genetics; Genomes; Genomics; Hospitals; Microscopy; Mutation; Next-generation sequencing; Population genetics; Primary ciliary dyskinesia; Proteins; Software; Ultrastructure; United Kingdom > UK; United States > US; California; mutation spectrum; cilia; bronchiectasis; primary ciliary dyskinesia; population
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2019-106501

BackgroundPrimary 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.MethodsThe diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.ResultsMost (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.ConclusionsThis 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.