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A novel homozygous complex deletion in CFTR caused cystic fibrosis in a Chinese patient

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Abstract

Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians, but is considered to be a very rare disease in Chinese population. Here, we present an 11-year-old Chinese CF patient with disseminated bronchiectasis and salty sweat, for whom exon sequencing followed by multiplex ligation-dependent probe amplification analysis of the CFTR gene was applied for mutation screening. A homozygous deletion involving exon 20 of CFTR was observed in the patient’s genome. Molecular characterization of the breakpoints indicated that both alleles of this locus had an identical novel complex rearrangement (c.3140-454_c.3367+249del931ins13, p.R1048_G1123del), leading to an in-frame removal of 76 amino acid residues in the second transmembrane domains of the CFTR protein. Although a same haplotype containing this complex rearrangement was observed on both of the maternal and paternal alleles, the parents denied any blood relationship as far as they know. Genome-wide homozygosity mapping was performed through SNP microarray and only a single homozygous interval of ~14.1 Mb at chromosome 7 containing the CFTR gene was observed, indicating the possible origin of the deletion from a common ancestor many generations ago. This study expands the mutation spectrum of CFTR in patients of Chinese origin and further emphasizes the necessity of MLPA analysis in mutation screening for CF patients.

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Abbreviations

CF:

Cystic fibrosis

CFTR:

Cystic fibrosis transmembrane conductance regulator

SNV:

Single-nucleotide variations

MLPA:

Multiplex ligation-dependent probe amplification

FEV1:

Forced expiratory volume in 1 s

FVC:

Forced vital capacity

CT:

Computed tomography

qPCR:

Quantitative real-time PCR

MAF:

Minor allele frequencies

TMD:

Transmembrane domain

References

  • Audrezet MP, Chen JM, Raguenes O, Chuzhanova N, Giteau K, Le Marechal C, Quere I, Cooper DN, Ferec C (2004) Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Hum Mutat 23:343–357

    Article  CAS  PubMed  Google Scholar 

  • Cer RZ, Donohue DE, Mudunuri US, Temiz NA, Loss MA, Starner NJ, Halusa GN, Volfovsky N, Yi M, Luke BT, Bacolla A, Collins JR, Stephens RM (2013) Non-B DB v2.0: a database of predicted non-B DNA-forming motifs and its associated tools. Nucleic Acids Res 41:D94–D100

    Article  CAS  PubMed  Google Scholar 

  • Chuzhanova N, Chen JM, Bacolla A, Patrinos GP, Ferec C, Wells RD, Cooper DN (2009) Gene conversion causing human inherited disease: evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair. Hum Mutat 30:1189–1198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colombo C, Littlewood J (2011) The implementation of standards of care in Europe: state of the art. J Cyst Fibros 10:S7–S15

    Article  PubMed  Google Scholar 

  • Fanen P, Wohlhuter-Haddad A, Hinzpeter A (2014) Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies. Int J Biochem Cell Biol 52:94–102

    Article  CAS  PubMed  Google Scholar 

  • Ferec C, Casals T, Chuzhanova N, Macek M Jr, Bienvenu T, Holubova A, King C, McDevitt T, Castellani C, Farrell PM, Sheridan M, Pantaleo SJ, Loumi O, Messaoud T, Cuppens H, Torricelli F, Cutting GR, Williamson R, Ramos MJ, Pignatti PF, Raguenes O, Cooper DN, Audrezet MP, Chen JM (2006) Gross genomic rearrangements involving deletions in the CFTR gene: characterization of six new events from a large cohort of hitherto unidentified cystic fibrosis chromosomes and meta-analysis of the underlying mechanisms. Eur J Hum Genet 14:567–576

    Article  CAS  PubMed  Google Scholar 

  • Feuillet-Fieux MN, Ferrec M, Gigarel N, Thuillier L, Sermet I, Steffann J, Lenoir G, Bonnefont JP (2004) Novel CFTR mutations in black cystic fibrosis patients. Clin Genet 65:284–287

    Article  CAS  PubMed  Google Scholar 

  • Guillot L, Beucher J, Tabary O, Le Rouzic P, Clement A, Corvol H (2014) Lung disease modifier genes in cystic fibrosis. Int J Biochem Cell Biol 52:83–93

    Article  CAS  PubMed  Google Scholar 

  • Hantash FM, Redman JB, Starn K, Anderson B, Buller A, McGinniss MJ, Quan F, Peng M, Sun W, Strom CM (2006) Novel and recurrent rearrangements in the CFTR gene: clinical and laboratory implications for cystic fibrosis screening. Hum Genet 119:126–136

    Article  CAS  PubMed  Google Scholar 

  • Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Wang L, Tian X, Xu K-F, Xu W, Li X, Yue C, Zhang P, Xiao Y, Zhang X (2015) Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology 20:312–318

    Article  PubMed  Google Scholar 

  • Magnani C, Cremonesi L, Giunta A, Magnaghi P, Taramelli R, Ferrari M (1996) Short direct repeats at the breakpoints of a novel large deletion in the CFTR gene suggest a likely slipped mispairing mechanism. Hum Genet 98:102–108

    Article  CAS  PubMed  Google Scholar 

  • Quemener S, Chen JM, Chuzhanova N, Benech C, Casals T, Macek M Jr, Bienvenu T, McDevitt T, Farrell PM, Loumi O, Messaoud T, Cuppens H, Cutting GR, Stenson PD, Giteau K, Audrezet MP, Cooper DN, Ferec C (2010) Complete ascertainment of intragenic copy number mutations (CNMs) in the CFTR gene and its implications for CNM formation at other autosomal loci. Hum Mutat 31:421–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073

    Article  CAS  PubMed  Google Scholar 

  • Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N et al (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245:1059–1065

    Article  CAS  PubMed  Google Scholar 

  • Seelow D, Schuelke M, Hildebrandt F, Nurnberg P (2009) HomozygosityMapper—an interactive approach to homozygosity mapping. Nucleic Acids Res 37:W593–W599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Y, Liu J, Zhong L, Mogayzel PJ Jr, Zeitlin PL, Sosnay PR, Zhao S (2016) Clinical phenotypes and genotypic spectrum of cystic fibrosis in chinese children. J Pediatr 171(269–276):e261

    Google Scholar 

  • Tang S, Moonnumakal SP, Stevens B, Douglas G, Mason S, Schmitt ES, Eng CM, Katz M, Fang P (2013) Characterization of a recurrent 3.8 kb deletion involving exons 17a and 17b within the CFTR gene. J Cyst Fibros 12:290–294

    Article  CAS  PubMed  Google Scholar 

  • The CF Foundation, Johns Hopkins University, The Hospital for Sick Children (2011) The Clinical and Functional TRanslation of CFTR (CFTR2) Database. http://www.cftr2.org. Accessed 1 Mar 2017

  • The International HapMap Consortium (2003) The international HapMap project. Nature 426:789–796

    Article  Google Scholar 

  • Tian X, Liu Y, Yang J, Wang H, Liu T, Xu W, Li X, Zhu Y, Xu KF, Zhang X (2016) p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var 3:15063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW (2004) Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 6:387–391

    Article  PubMed  PubMed Central  Google Scholar 

  • Wells RD (2007) Non-B DNA conformations, mutagenesis and disease. Trends Biochem Sci 32:271–278

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Huang X, Liang Y, Xu L, Pei Y, Cheng Y, Zhang L, Tang W (2015) A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis. Clin Respir J. doi:10.1111/crj.12401

    Google Scholar 

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Acknowledgements

We are grateful to the patient and her family for their contributions to this work. The research was supported by the National Natural Science Foundation of China (31271345) to Yaping Liu; Beijing Municipal Science and Technology Commission (Z151100003915078) and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002) to Xue Zhang.

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Author notes

  1. Keqiang Liu and Yaping Liu contributed equally to this article.

  2. Yaping Liu, Xinlun Tian and Xue Zhang contributed equally for study design and supervision in this article.

Authors and Affiliations

  1. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China

    Keqiang Liu, Yaping Liu & Xue Zhang

  2. Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China

    Xue Li, Kai-Feng Xu & Xinlun Tian

Authors
  1. Keqiang Liu
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  2. Yaping Liu
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  3. Xue Li
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  4. Kai-Feng Xu
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  5. Xinlun Tian
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  6. Xue Zhang
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Corresponding author

Correspondence to Yaping Liu.

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Conflict of interest

The authors declare that they have no competing interest.

Ethics approval and consent to participate

The protocol of this study was approved by the Institutional Review Board committee at PUMCH. Signed informed consents were obtained from all individual participants included in the study.

Additional information

Communicated by S. Hohmann.

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Liu, K., Liu, Y., Li, X. et al. A novel homozygous complex deletion in CFTR caused cystic fibrosis in a Chinese patient. Mol Genet Genomics 292, 1083–1089 (2017). https://doi.org/10.1007/s00438-017-1334-0

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  • DOI: https://doi.org/10.1007/s00438-017-1334-0

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