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