Mitchison, H;
(2019)
Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort.
Journal of Medical Genetics
10.1136/jmedgenet-2019-106501.
(In press).
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Text (Article)
Mitchison_Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort_AAM2.pdf - Accepted Version Download (1MB) | Preview |
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Text (Supplementary Material)
Mitchison_Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort_SuppM.pdf - Accepted Version Download (1MB) | Preview |
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.
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