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

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

doi:10.1136/jmedgenet-2019-106501

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

Mahmoud R. Fassad, Mitali P. Patel, Amelia Shoemark, Thomas Cullup, Jane Hayward, Mellisa Dixon, Andrew V. Rogers, Sarah Ollosson, Claire Jackson, Patricia Goggin, Robert A. Hirst, Andrew Rutman, James Thompson, Lucy Jenkins, Paul Aurora, Eduardo Moya, Philip Chetcuti, Chris O'Callaghan, Deborah J. Morris-Rosendahl, Christopher M. WatsonRobert Wilson, Siobhan Carr, Woolf Walker, Andreia Pitno, Susana Lopes, Heba Morsy, Walaa Shoman, Luisa Pereira, Carolina Constant, Michael R. Loebinger, Eddie M. K. Chung, Priti Kenia, Nisreen Rumman, Nader Fasseeh, Jane S. Lucas, Claire Hogg, Hannah M. Mitchison (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	322-330
Number of pages	9
Journal	Journal of Medical Genetics
Volume	57
Issue number	5
Early online date	25 Dec 2019
DOIs	https://doi.org/10.1136/jmedgenet-2019-106501
Publication status	Published - 23 Apr 2020

Keywords

bronchiectasis
cilia
mutation spectrum
population
primary ciliary dyskinesia

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Fassad, M. R., Patel, M. P., Shoemark, A., Cullup, T., Hayward, J., Dixon, M., Rogers, A. V., Ollosson, S., Jackson, C., Goggin, P., Hirst, R. A., Rutman, A., Thompson, J., Jenkins, L., Aurora, P., Moya, E., Chetcuti, P., O'Callaghan, C., Morris-Rosendahl, D. J., ... Mitchison, H. M. (2020). Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. Journal of Medical Genetics, 57(5), 322-330. https://doi.org/10.1136/jmedgenet-2019-106501

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title = "Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort",

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.",

keywords = "bronchiectasis, cilia, mutation spectrum, population, primary ciliary dyskinesia",

author = "Fassad, {Mahmoud R.} and Patel, {Mitali P.} and Amelia Shoemark and Thomas Cullup and Jane Hayward and Mellisa Dixon and Rogers, {Andrew V.} and Sarah Ollosson and Claire Jackson and Patricia Goggin and Hirst, {Robert A.} and Andrew Rutman and James Thompson and Lucy Jenkins and Paul Aurora and Eduardo Moya and Philip Chetcuti and Chris O'Callaghan and Morris-Rosendahl, {Deborah J.} and Watson, {Christopher M.} and Robert Wilson and Siobhan Carr and Woolf Walker and Andreia Pitno and Susana Lopes and Heba Morsy and Walaa Shoman and Luisa Pereira and Carolina Constant and Loebinger, {Michael R.} and Chung, {Eddie M. K.} and Priti Kenia and Nisreen Rumman and Nader Fasseeh and Lucas, {Jane S.} and Claire Hogg and Mitchison, {Hannah M.}",

year = "2020",

month = apr,

day = "23",

doi = "10.1136/jmedgenet-2019-106501",

language = "English",

volume = "57",

pages = "322--330",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "5",

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Fassad, MR, Patel, MP, Shoemark, A, Cullup, T, Hayward, J, Dixon, M, Rogers, AV, Ollosson, S, Jackson, C, Goggin, P, Hirst, RA, Rutman, A, Thompson, J, Jenkins, L, Aurora, P, Moya, E, Chetcuti, P, O'Callaghan, C, Morris-Rosendahl, DJ, Watson, CM, Wilson, R, Carr, S, Walker, W, Pitno, A, Lopes, S, Morsy, H, Shoman, W, Pereira, L, Constant, C, Loebinger, MR, Chung, EMK, Kenia, P, Rumman, N, Fasseeh, N, Lucas, JS, Hogg, C & Mitchison, HM 2020, 'Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort', Journal of Medical Genetics, vol. 57, no. 5, pp. 322-330. https://doi.org/10.1136/jmedgenet-2019-106501

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

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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 -

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

Abstract

Keywords

ASJC Scopus subject areas

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