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

Mahmoud R Fassad^{1

2}, Mitali P Patel¹, Amelia Shoemark^{3

4}, Thomas Cullup⁵, Jane Hayward⁵, Mellisa Dixon³, Andrew V Rogers⁶, Sarah Ollosson³, Claire Jackson^{7

8}, Patricia Goggin^{7

8}, Robert A Hirst⁹, Andrew Rutman⁹, James Thompson^{7

8}, Lucy Jenkins⁵, Paul Aurora^{10

11}, Eduardo Moya¹², Philip Chetcuti¹³, Chris O'Callaghan^{9

11}, Deborah J Morris-Rosendahl¹⁴, Christopher M Watson¹⁵, Robert Wilson⁶, Siobhan Carr³, Woolf Walker^{7

8}, Andreia Pitno^{3

16}, Susana Lopes¹⁷, Heba Morsy², Walaa Shoman¹⁸, Luisa Pereira¹⁹, Carolina Constant¹⁹, Michael R Loebinger⁶, Eddie M K Chung²⁰, Priti Kenia²¹, Nisreen Rumman²², Nader Fasseeh¹⁸, Jane S Lucas^{7

8}, Claire Hogg³, Hannah M Mitchison²³

Affiliations

¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
² Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
³ PCD Diagnostic Team and Department of Pediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
⁴ Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
⁵ NE Thames Regional Molecular Genetics Laboratory, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK.
⁶ Host Defence Unit, Royal Brompton and Harefield NHS Trust, London, UK.
⁷ Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust and Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine, Southampton, UK.
⁸ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁹ Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
¹⁰ Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹¹ Department of Respiratory, Critical Care and Anaesthesia Unit, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
¹² Children's Services (Paediatrics), Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
¹³ Department of Respiratory Paediatrics, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁴ Clinical Genetics and Genomics Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
¹⁵ Leeds Genetics Laboratory, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁶ Laboratório de Histologia e Patologia Comparada, Instituto de Medicina Molecular, Centro Académico de Medicina de Lisboa, Lisbon, Portugal.
¹⁷ CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
¹⁸ Department of Pediatrics, Faculty of Medicine, Alexandria University Children's Hospital, Alexandria, Egypt.
¹⁹ Paediatric Pulmonology Unit, Department of Pediatrics, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, Lisbon, Portugal.
²⁰ Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
²¹ Department of Respiratory Paediatrics, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
²² Pediatrics Department, Makassed Hospital, East Jerusalem, Israel.
²³ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK h.mitchison@ucl.ac.uk.

PMID: 31879361
DOI: 10.1136/jmedgenet-2019-106501

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

Mahmoud R Fassad et al. J Med Genet. 2020 May.

. 2020 May;57(5):322-330.

doi: 10.1136/jmedgenet-2019-106501. Epub 2019 Dec 25.

Authors

Affiliations

¹ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
² Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
³ PCD Diagnostic Team and Department of Pediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
⁴ Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
⁵ NE Thames Regional Molecular Genetics Laboratory, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK.
⁶ Host Defence Unit, Royal Brompton and Harefield NHS Trust, London, UK.
⁷ Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust and Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine, Southampton, UK.
⁸ NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁹ Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
¹⁰ Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹¹ Department of Respiratory, Critical Care and Anaesthesia Unit, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
¹² Children's Services (Paediatrics), Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
¹³ Department of Respiratory Paediatrics, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁴ Clinical Genetics and Genomics Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
¹⁵ Leeds Genetics Laboratory, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁶ Laboratório de Histologia e Patologia Comparada, Instituto de Medicina Molecular, Centro Académico de Medicina de Lisboa, Lisbon, Portugal.
¹⁷ CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
¹⁸ Department of Pediatrics, Faculty of Medicine, Alexandria University Children's Hospital, Alexandria, Egypt.
¹⁹ Paediatric Pulmonology Unit, Department of Pediatrics, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, Lisbon, Portugal.
²⁰ Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
²¹ Department of Respiratory Paediatrics, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
²² Pediatrics Department, Makassed Hospital, East Jerusalem, Israel.
²³ Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK h.mitchison@ucl.ac.uk.

PMID: 31879361
DOI: 10.1136/jmedgenet-2019-106501

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.

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Conflict of interest statement

Competing interests: None declared.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical