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Genetic Analysis of Korean Adult Patients with Nontuberculous Mycobacteria Suspected of Primary Ciliary Dyskinesia Using Whole Exome Sequencing

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Purpose: Nontuberculous mycobacteria (NTM) is ubiquitous in the environment, but NTM lung disease (NTM-LD) is uncommon. Since exposure to NTM is inevitable, patients who develop NTM-LD are likely to have specific susceptibility factors, such as primary ciliary dyskinesia (PCD). PCD is a genetically heterogeneous disorder of motile cilia and is characterized by chronic respiratory tract infection, organ laterality defect, and infertility. In this study, we performed whole exome sequencing (WES) and investigated the genetic characteristics of adult NTM patients with suspected PCD. Materials and Methods: WES was performed in 13 NTM-LD patients who were suspected of having PCD by clinical symptoms and/or ultrastructural ciliary defect observed by transmission electron microscopy. A total of 45 PCD-causing genes, 23 PCDcandidate genes, and 990 ciliome genes were analyzed. Results: Four patients were found to have biallelic loss-of-function (LoF) variants in the following PCD-causing genes: CCDC114, DNAH5, HYDIN, and NME5. In four other patients, only one LoF variant was identified, while the remaining five patients did not have any LoF variants. Conclusion: At least 30.8% of NTM-LD patients who were suspected of having PCD had biallelic LoF variants, and an additional 30.8% of patients had one LoF variant. Therefore, PCD should be considered in patients with NTM-LD with symptoms or signs suspicious of PCD.

Abstract

Purpose: Nontuberculous mycobacteria (NTM) is ubiquitous in the environment, but NTM lung disease (NTM-LD) is uncommon. Since exposure to NTM is inevitable, patients who develop NTM-LD are likely to have specific susceptibility factors, such as primary ciliary dyskinesia (PCD). PCD is a genetically heterogeneous disorder of motile cilia and is characterized by chronic respiratory tract infection, organ laterality defect, and infertility. In this study, we performed whole exome sequencing (WES) and investigated the genetic characteristics of adult NTM patients with suspected PCD. Materials and Methods: WES was performed in 13 NTM-LD patients who were suspected of having PCD by clinical symptoms and/or ultrastructural ciliary defect observed by transmission electron microscopy. A total of 45 PCD-causing genes, 23 PCDcandidate genes, and 990 ciliome genes were analyzed. Results: Four patients were found to have biallelic loss-of-function (LoF) variants in the following PCD-causing genes: CCDC114, DNAH5, HYDIN, and NME5. In four other patients, only one LoF variant was identified, while the remaining five patients did not have any LoF variants. Conclusion: At least 30.8% of NTM-LD patients who were suspected of having PCD had biallelic LoF variants, and an additional 30.8% of patients had one LoF variant. Therefore, PCD should be considered in patients with NTM-LD with symptoms or signs suspicious of PCD.

참고문헌 (38)

  1. Falkinham JO 3rd, "Environmental sources of nontuberculous mycobacteria", Clin Chest Med, 36, pp.35~41 (2015)
  2. Wu UI, "Host susceptibility to non-tuberculous mycobacterial infections", Lancet Infect Dis, 15, pp.968~980 (2015)
  3. Fliegauf M, "When cilia go bad : cilia defects and ciliopathies", Nat Rev Mol Cell Biol, 8, pp.880~893 (2007)
  4. Leigh MW, "Clinical and genetic aspects of primary ciliary dyskinesia", Kartagener syndrome, 2009, pp.11, 473~487
  5. Yoshiba S, "Cilia at the node of mouse embryos sense fluid flow for leftright determination via Pkd2", Science, 338, pp.226~231 (2012)
  6. Wang G, "Analysis of gene function and visualization of cilia-generated fluid flow in Kupffer’s vesicle", J Vis Exp, (73), pp.50038~ (2013)
  7. Noone PG, "Primary ciliary dyskinesia : diagnostic and phenotypic features", Am J Respir Crit Care Med, 169, pp.459~467 (2004)
  8. Fowler CJ, "Abnormal nasal nitric oxide production, ciliary beat frequency, and Toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium", Am J Respir Crit Care Med, 187, pp.1374~1381 (2013)
  9. Saleeb P, "Pulmonary nontuberculous mycobacterial disease : new insights into risk factors for susceptibility, epidemiology, and approaches to management in immunocompetent and immunocompromised patients", Curr Infect Dis Rep, 12, pp.198~203 (2010)
  10. McShane PJ, "Pulmonary disease due to nontuberculous mycobacteria : current state and new insights", Chest, 148, pp.1517~1527 (2015)
  11. Mullowney T, "Primary ciliary dyskinesia and neonatal respiratory distress", Pediatrics, 134, pp.1160~1166 (2014)
  12. Kuehni CE, "Factors influencing age at diagnosis of primary ciliary dyskinesia in European children", Eur Respir J, 36, pp.1248~1258 (2010)
  13. Braun JJ, "Diagnosis of primary ciliary dyskinesia: when and how?", Eur Ann Otorhinolaryngol Head Neck Dis, 134, pp.377~382 (2017)
  14. Shoemark A, "Aetiology in adult patients with bronchiectasis", Respir Med, 101, pp.1163~1170 (2007)
  15. Lonni S, "Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity", Ann Am Thorac Soc, 12, pp.1764~1770 (2015)
  16. Amorim A, "Bronchiectasis: a retrospective study of clinical and aetiological investigation in a general respiratory department", Rev Port Pneumol(2006), 21, pp.5~10 (2015)
  17. Verra F, "Inherited factors in diffuse bronchiectasis in the adult : a prospective study", Eur Respir J, 4, pp.937~944 (1991)
  18. Pasteur MC, "An investigation into causative factors in patients with bronchiectasis", Am J Respir Crit Care Med, 162(4 Pt 1), pp.1277~1284 (2000)
  19. Qi Q, "Aetiology and clinical characteristics of patients with bronchiectasis in a Chinese Han population : a prospective study", Respirology, 20, pp.917~924 (2015)
  20. Guan WJ, "Aetiology of bronchiectasis in Guangzhou, southern China", Respirology, 20, pp.739~748 (2015)
  21. Dimakou K, "Non CF-bronchiectasis : aetiologic approach, clinical, radiological, microbiological and functional profile in 277 patients", Respir Med, 116, pp.1~7 (2016)
  22. Olveira C, "Etiology of bronchiectasis in a cohort of 2047 patients. An analysis of the Spanish historical bronchiectasis registry", Arch Bronconeumol, 53, pp.366~374 (2017)
  23. Griffith DE, "An official ATS", IDSA statement : diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, 2007, pp.175, 367~416
  24. Shapiro AJ, "Diagnosis, monitoring, and treatment of primary ciliary dyski-nesia : PCD foundation consensus recommendations based on state of the art review", Pediatr Pulmonol, 51, pp.115~132 (2016)
  25. Li Y, "DNAH6 and its interactions with PCD Genes in heterotaxy and primary ciliary dyskinesia", PLoS Genet, 12, pp.e1005821~ (2016)
  26. Richards S, "Standards and guidelines for the interpretation of sequence variants : a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)
  27. Cho EH, "A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects", Clin Genet, 98, pp.64~68 (2020)
  28. Takeuchi K, "A targeted next-generation sequencing panel reveals novel mutations in Japanese patients with primary ciliary dyskinesia", Auris Nasus Larynx, 45, pp.585~591 (2018)
  29. Hornef N, "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects", Am J Respir Crit Care Med, 174, pp.120~126 (2006)
  30. Berg JS, "Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia : implications for application to clinical testing", Genet Med, 13, pp.218~229 (2011)
  31. Pigino G, "Cryoelectron tomography of radial spokes in cilia and flagella", J Cell Biol, 195, pp.673~687 (2011)
  32. Knowles MR, "Exome sequencing identifies mutations in CCDC114as a cause of primary ciliary dyskinesia", Am J Hum Genet, 92, pp.99~106 (2013)
  33. Omran H, "Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene", Am J Respir Cell Mol Biol, 23, pp.696~702 (2000)
  34. Olbrich H, "Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry", Am J Hum Genet, 91, pp.672~684 (2012)
  35. Paff T, "Diagnostic yield of a targeted gene panel in primary ciliary dyskinesia patients", Hum Mutat, 39, pp.653~665 (2018)
  36. Abou Tayoun AN, "Recommendations for interpreting the loss of function PVS1 ACMG", AMP variant criterion, 2018, pp.39, 1517~1524
  37. Gopal R, "The DPY-30 domain and its flanking sequence mediate the assembly and modulation of flagellar radial spoke complexes", Mol Cell Biol, 32, pp.4012~4024 (2012)
  38. Hirst RA, "Ciliated air-liquid cultures as an aid to diagnostic testing of primary ciliary dyskinesia", Chest, 138, pp.1441~1447 (2010)

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