TY - JOUR
T1 - Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort
AU - Fassad, Mahmoud R.
AU - Patel, Mitali P.
AU - Shoemark, Amelia
AU - Cullup, Thomas
AU - Hayward, Jane
AU - Dixon, Mellisa
AU - Rogers, Andrew V.
AU - Ollosson, Sarah
AU - Jackson, Claire
AU - Goggin, Patricia
AU - Hirst, Robert A.
AU - Rutman, Andrew
AU - Thompson, James
AU - Jenkins, Lucy
AU - Aurora, Paul
AU - Moya, Eduardo
AU - Chetcuti, Philip
AU - O'Callaghan, Chris
AU - Morris-Rosendahl, Deborah J.
AU - Watson, Christopher M.
AU - Wilson, Robert
AU - Carr, Siobhan
AU - Walker, Woolf
AU - Pitno, Andreia
AU - Lopes, Susana
AU - Morsy, Heba
AU - Shoman, Walaa
AU - Pereira, Luisa
AU - Constant, Carolina
AU - Loebinger, Michael R.
AU - Chung, Eddie M. K.
AU - Kenia, Priti
AU - Rumman, Nisreen
AU - Fasseeh, Nader
AU - Lucas, Jane S.
AU - Hogg, Claire
AU - Mitchison, Hannah M.
PY - 2020/4/23
Y1 - 2020/4/23
N2 - 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.
AB - 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.
KW - bronchiectasis
KW - cilia
KW - mutation spectrum
KW - population
KW - primary ciliary dyskinesia
UR - http://www.scopus.com/inward/record.url?scp=85077217284&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2019-106501
DO - 10.1136/jmedgenet-2019-106501
M3 - Article
C2 - 31879361
AN - SCOPUS:85077217284
SN - 0022-2593
VL - 57
SP - 322
EP - 330
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 5
ER -