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Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort

Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort
Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort
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.
bronchiectasis, cilia, mutation spectrum, population, primary ciliary dyskinesia
0022-2593
322-330
Fassad, Mahmoud R.
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Patel, Mitali
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Shoemark, Amelia
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Cullup, Thomas
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Hayward, Jane
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Dixon, Mellisa
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Rogers, Andrew V.
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Ollosson, Sarah
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Jackson, Claire
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Goggin, Patricia, Mary
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Hirst, Robert A.
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Rutman, Andrew
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Thompson, James
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Jenkins, Lucy
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Aurora, Paul
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Mova, Eduardo
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Chetcuti, Philip
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O'Callaghan, Christopher
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Morris-Rosendahl, Deborah
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Watson, Christopher M.
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Wilson, Robert
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Carr, Siobhan
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Walker, Woolf
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Pinto, Andreia
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Lopes, Susana P.
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Morsy, Heba
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Shoman, Walaa
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Pereira, Luísa
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Constant, Carolina
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Loebinger, Michael R.
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Chung, Eddie M.K.
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Kenia, Priti
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Rumman, Nisreen
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Fasseeh, Nader
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Lucas, Jane
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Hogg, Claire
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Mitchison, Hannah
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Fassad, Mahmoud R.
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Patel, Mitali
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Shoemark, Amelia
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Cullup, Thomas
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Hayward, Jane
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Dixon, Mellisa
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Rogers, Andrew V.
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Ollosson, Sarah
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Jackson, Claire
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Goggin, Patricia, Mary
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Hirst, Robert A.
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Rutman, Andrew
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Thompson, James
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Jenkins, Lucy
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Aurora, Paul
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Mova, Eduardo
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Chetcuti, Philip
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O'Callaghan, Christopher
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Morris-Rosendahl, Deborah
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Watson, Christopher M.
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Wilson, Robert
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Carr, Siobhan
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Walker, Woolf
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Pinto, Andreia
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Lopes, Susana P.
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Morsy, Heba
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Shoman, Walaa
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Pereira, Luísa
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Constant, Carolina
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Loebinger, Michael R.
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Chung, Eddie M.K.
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Kenia, Priti
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Rumman, Nisreen
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Fasseeh, Nader
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Lucas, Jane
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Hogg, Claire
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Mitchison, Hannah
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Fassad, Mahmoud R., Patel, Mitali, Shoemark, Amelia, Cullup, Thomas, Hayward, Jane, Dixon, Mellisa, Rogers, Andrew V., Ollosson, Sarah, Jackson, Claire, Goggin, Patricia, Mary, Hirst, Robert A., Rutman, Andrew, Thompson, James, Jenkins, Lucy, Aurora, Paul, Mova, Eduardo, Chetcuti, Philip, O'Callaghan, Christopher, Morris-Rosendahl, Deborah, Watson, Christopher M., Wilson, Robert, Carr, Siobhan, Walker, Woolf, Pinto, Andreia, Lopes, Susana P., Morsy, Heba, Shoman, Walaa, Pereira, Luísa, Constant, Carolina, Loebinger, Michael R., Chung, Eddie M.K., Kenia, Priti, Rumman, Nisreen, Fasseeh, Nader, Lucas, Jane, Hogg, Claire and Mitchison, Hannah (2020) Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort. Journal of Medical Genetics, 57 (5), 322-330. (doi:10.1136/jmedgenet-2019-106501).

Record type: Article

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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Accepted/In Press date: 1 November 2019
e-pub ahead of print date: 25 December 2019
Published date: 31 May 2020
Keywords: bronchiectasis, cilia, mutation spectrum, population, primary ciliary dyskinesia

Identifiers

Local EPrints ID: 435833
URI: http://eprints.soton.ac.uk/id/eprint/435833
ISSN: 0022-2593
PURE UUID: b677114f-6b6e-4f3d-9b69-7238a5833643
ORCID for Patricia, Mary Goggin: ORCID iD orcid.org/0000-0003-4730-0206

Catalogue record

Date deposited: 21 Nov 2019 17:30
Last modified: 26 Nov 2021 05:54

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Contributors

Author: Mahmoud R. Fassad
Author: Mitali Patel
Author: Amelia Shoemark
Author: Thomas Cullup
Author: Jane Hayward
Author: Mellisa Dixon
Author: Andrew V. Rogers
Author: Sarah Ollosson
Author: Claire Jackson
Author: Patricia, Mary Goggin ORCID iD
Author: Robert A. Hirst
Author: Andrew Rutman
Author: James Thompson
Author: Lucy Jenkins
Author: Paul Aurora
Author: Eduardo Mova
Author: Philip Chetcuti
Author: Christopher O'Callaghan
Author: Deborah Morris-Rosendahl
Author: Christopher M. Watson
Author: Robert Wilson
Author: Siobhan Carr
Author: Woolf Walker
Author: Andreia Pinto
Author: Susana P. Lopes
Author: Heba Morsy
Author: Walaa Shoman
Author: Luísa Pereira
Author: Carolina Constant
Author: Michael R. Loebinger
Author: Eddie M.K. Chung
Author: Priti Kenia
Author: Nisreen Rumman
Author: Nader Fasseeh
Author: Jane Lucas
Author: Claire Hogg
Author: Hannah Mitchison

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