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About CF » CFTR mutations » The correlation between CFTR mutations and disease severity » CFTR genotype

CFTR genotype

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CF symptoms are highly varied among individual patients, even between siblings who carry identical CFTR alleles. This variation is thought to be influenced by non-genetic factors (e.g. the environment) and by genes that can act on the CFTR gene (i.e. modifier genes).1-3

CFTR genotype

  • The clinical symptoms of the CFTR gene defect range from mild to severe
  • This relates to the functionality of each CFTR allele and therefore the amount of transmembrane Cl transport4
  • Patients with two CFTR mutations of classes I, II, III and VI tend to have severe CF, whereas mutation classes IV or V are usually associated with  residual function of  CFTR protein4,5

CFTR genotype: Severe/severe CFTR mutations

Two severe CFTR gene mutations significantly limit Cl transport due to:

  • Reduced quantity of CFTR channel in the cell membrane and/or
  • Limited function of CFTR channel due to a gating or conductance defect
Phenotype of severe CFTR mutations


  • Pancreatic insufficiency
  • Severe lung function deterioration
  • Higher frequency of meconium ileus and premature mortality
  • Higher incidence of malnutrition and severe liver disease

Common mutations

  • F508del/F508del
  • F508del/G551D
  • R553X/G542X

CFTR genotype: Severe/mild CFTR mutations

  • One severe CFTR mutation significantly limits Cl transport
  • One mild CFTR mutation allows slight Cl transport, for example, due to a conductance defect
Phenotype of relatively severe CFTR mutations


  • Pancreatic sufficiency
  • Milder lung disease
  • Greater life expectancy
  • Reduced probability to develop serious gastrointestinal complications or CF-related diabetes

Common mutations

  • F508del/3489 + 10kb C→T
  • G551D/R117H
  • F508del/A455E

CFTR genotype: Mild/mild CFTR mutations

  • Two mild CFTR mutant alleles allow slight Cl transport
  • In some cases, the CF ‘sufferer’ may not be diagnosed as he/she is asymptomatic4
Phenotype of mild CFTR mutations


  • Pancreatic sufficiency
  • Milder lung disease
  • Greater life expectancy
  • Highly unlikely to develop meconium ileus, serious GI complications or CF-related diabetes

Common mutations

  • 3489 + 10kb C→T/3489 + 10kb C→T
  • 3489 + 10kb C→T/R347P
  • 2789 + 5 G→A/R334W

CFTR genotype: Conclusion

Close-up of a pancreasIn conclusion, there is a correlation between CFTR genotype and phenotype:

  • The evidence for this correlation is strongest for pancreatic status
  • The correlation between lung function and CFTR genotype is more variable1, 2, 5
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  1. Zielenski J. Respiration 2000;67:117–33
  2. Castellani C et al. J Cyst Fibros 2008;7:179–96
  3. Rowntree R et al. Ann Hum Genet 2003;67:471–85
  4. Koch C et al. Pulmonol 2001;31:1–12
  5. Wilschanski M et al. Gut 2007;56:1153–63
  6. Colombo C et al. Paediatr 2007;96:477–9
  7. CFTR2 database. Accessed 15 October 2012
  8. Comer DM et al. QJM 2009;102:793–8
  9. Moskowitz S et al. CFTR-Related Disorders. Cystic Fibrosis and Congenital Absence of the Vas Deferens. GeneReviews [Internet].  University of Washington, Seattle 1993. Last update 19 February 2008
  10. Dohle G et al. Hum Reprod 1999;14:371–4
  11. Thauvin-Robinet C et al. J Med Genet 2009;46:752–8