Correspondence

Correlation between Genotype and Phenotype in Patients with Cystic Fibrosis

N Engl J Med 1994; 330:865-867March 24, 1994

Article

To the Editor:

In a recent article Hamosh and Corey of the Cystic Fibrosis Genotype-Phenotype Consortium (Oct. 28 issue)1 reported on correlations between the genotypes and phenotypes of patients with cystic fibrosis. The mean age of the patients with the R117H/ΔF₅₀₈ genotype was 23.5 years, and the ages of the other groups ranged from 11.0 to 14.6 years. The authors conclude that genotype is predictive of pancreatic status but not of the severity of pulmonary disease.

In our adult patient population, however, we found a correlation between the genotype and the severity of pulmonary disease. The rate of decline in lung function was faster in ΔF₅₀₈ homozygotes and in heterozygotes for ΔF₅₀₈ and certain “severe” mutations. On the other hand, certain “mild” mutations were associated with milder pulmonary disease, leading to a less rapid decline in lung function.

We recently analyzed DNA from 114 adult patients with cystic fibrosis, mainly from western and central parts of the Netherlands. Among our patients the A455E mutation was relatively frequent (found in 13 of the 114 patients); this mutation has not been found this often, except among French Canadian patients2. We found marked clinical differences between patients with different cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations (Table 1Table 1Clinical Characteristics of Patients with Cystic Fibrosis and Various Genotypes.).

The clinical features and the age at diagnosis of the patients with the ΔF₅₀₈/ΔF₅₀₈ genotype and those with the ΔF₅₀₈/nonsense genotype were essentially the same. Among the patients with the ΔF₅₀₈/A455E and the A455E/other genotype, pancreatic insufficiency was less frequent (as previously reported3) and lung function was significantly better. In addition, patients with an A455E mutation were significantly older at diagnosis. There was no difference in phenotype between the patients with the ΔF₅₀₈/A455E genotype and those with the A455E/other genotype.

We conclude that the presence of an A455E mutation in a patient with cystic fibrosis is associated with, and therefore predictive of, mild pulmonary disease and greater pancreatic sufficiency.

K.H. Gan, M.D.
H.G.M. Heijerman, M.D., Ph.D.
W. Bakker, M.D., Ph.D.
Leyenburg Hospital, 2545 CH The Hague, the Netherlands

3 References

1. 1

   The Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med 1993;329:1308-1313
   Full Text | Web of Science | Medline

2. 2

   Rozen R, De Braekeleer M, Daigneault J, et al. Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis. Am J Med Genet 1992;42:360-364
   CrossRef | Web of Science | Medline

3. 3

   Kristidis P, Bozon D, Corey M, et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992;50:1178-1184
   Web of Science | Medline

To the Editor:

The members of the Cystic Fibrosis Genotype-Phenotype Consortium conclude that patients with cystic fibrosis and the R117H/ΔF₅₀₈ genotype will have long-term pancreatic sufficiency, whereas patients with other genotypes will have early-onset pancreatic insufficiency. In 1991 Highsmith et al.1 described a woman with mild disease who had a splice-site mutation in intron 19, designated 3849+10kb C-to-T. Recently we have reported2 on 15 patients with this mutation. All were Ashkenazi Jews. We compared their clinical features with those of patients with cystic fibrosis who had the ΔF₅₀₈/ΔF₅₀₈, W1282X/W1282X, or W1282X/ΔF₅₀₈ mutations, which are known to be associated with a severe disease. Patients with the 3849+10kb C-to-T mutation were currently older, had been older at diagnosis, and were in a better nutritional state in terms of weight and height percentiles. Five patients (33 percent) had normal sweat chloride levels (<60 mmol per liter), and 10 (66 percent) had sufficient pancreatic function to maintain fat absorption. None of the patients with the 3849+10kb C-to-T mutation had had meconium ileus or had liver disease or diabetes mellitus. However, the two groups studied did not differ in their age-adjusted pulmonary function. Our findings concerning the 3849+10kb C-to-T mutation are similar to those concerning the R117H mutation.

Arie Augarten, M.D.
Sheba Medical Center, Ramat Gan, Israel

Bat-Sheva Kerem, Ph.D.
Hebrew University

Eitan Kerem, M.D.
Shaare Zedek Hospital, Jerusalem, Israel

Ephraim Gazit, M.D.
Yaacov Yahav, M.D.
Sheba Medical Center, Ramat Gan, Israel

2 References

1. 1

   Highsmith WE, Burch LH, Boat TF, Boucher RC, Silverman LM, Knowles MR. Identification of a homozygous point mutation in intron 19 in an inbred CF patient with mild disease and normal sweat chloride: creation of an alternative splice site resulting in base-sequence insertion in CFTR coding region between exon 19 and 20. Pediatr Pulmonol 1991;6:22A-22A
   

2. 2

   Augarten A, Kerem B-S, Yahav Y, et al. Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849+10kb C-to-T mutation. Lancet 1993;342:25-26
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Gan and colleagues report that the A455E mutation compounded with ΔF₅₀₈ for other CFTR mutations was associated with mild pulmonary disease and pancreatic sufficiency in their adult patients. A correlation between pulmonary status and genotype was suggested before the CFTR gene was identified1 and in the initial studies of the effect of the ΔF₅₀₈ mutation on phenotype2. We did not see a difference in pulmonary function when comparing ΔF₅₀₈ homozygotes with R117H/ΔF₅₀₈ compound heterozygotes. There are many possible reasons for this. The ranges for age and pulmonary function in each genotype group were very broad, which would have tended to make subtle differences less obvious. Also, the multinational, cross-sectional nature of the study may have obscured specific genetic or environmental factors that might preserve lung function in an ethnic isolate. Finally, since this study was performed, it was discovered that the R117H mutation occurred on two different chromosome backgrounds,3 one of which is likely to be associated with inefficient splicing of CFTR messenger RNA, leading to decreased quantities of partially functional protein. Patients with both types of chromosome backgrounds would have been included in the analysis of the Cystic Fibrosis Genotype-Phenotype Consortium.

The study by Gan and colleagues suggests that analysis of additional CFTR mutations associated with pancreatic sufficiency may identify other mutations associated with mild pulmonary disease. However, variability among individuals is great, and care should be taken in attempting to predict the onset or course of pulmonary disease in individual patients with cystic fibrosis.

Ada Hamosh, M.D., M.P.H.
Johns Hopkins University School of Medicine, Baltimore, MD 21287-4922

Mary Corey, Ph.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

3 References

1. 1

   Gaskin K, Gurwitz D, Durie P, Corey M, Levison H, Forstner G. Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption. J Pediatr 1982;100:857-862
   CrossRef | Web of Science | Medline

2. 2

   Kerem E, Corey M, Kerem B-S, et al. The relation between genotype and phenotype in cystic fibrosis -- analysis of the most common mutation (ΔF₅₀₈). N Engl J Med 1990;323:1517-1522
   Full Text | Web of Science | Medline

3. 3

   Kiesewetter S, Macek M Jr, Davis C, et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nature Genet 1993;5:274-277
   CrossRef | Web of Science | Medline

Citing Articles (8)

Citing Articles

1. 1

   Ingrid Duguépéroux, Marc De Braekeleer. (2004) Genotype–phenotype relationship for five CFTR mutations frequently identified in western France. Journal of Cystic Fibrosis 3:4, 259-263
   CrossRef

2. 2

   John E. Mickle, Garry R. Cutting. (2000) GENOTYPE-PHENOTYPE RELATIONSHIPS IN CYSTIC FIBROSIS. Medical Clinics of North America 84:3, 597-607
   CrossRef

3. 3

   Yoshihiko Maehara, Yoshihiro Kakeji, Akihiro Watanabe, Hideo Baba, Hiroki Kusumoto, Shunji Kohnoe, Keizo Sugimachi. (1999) Clinical implications of serum anti-p53 antibodies for patients with gastric carcinoma. Cancer 85:2, 302-308
   CrossRef

4. 4

   John E. Mickle, Garry R. Cutting. (1998) CLINICAL IMPLICATIONS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATIONS. Clinics in Chest Medicine 19:3, 443-458
   CrossRef

5. 5

   LISA S. PARKER, RACHEL ANKENY MAJESKE. (1996) Standards of Care and Ethical Concerns in Genetic Testing and Screening. Clinical Obstetrics and Gynecology 39:4, 873-884
   CrossRef

6. 6

   BABETTE S. ZEMEL, DEBORAH A. KAWCHAK, AVITAL CNAAN, HUAQING ZHAO, THOMAS F. SCANLIN, VIRGINIA A. STALLINGS. (1996) Prospective Evaluation of Resting Energy Expenditure, Nutritional Status, Pulmonary Function, and Genotype in Children with Cystic Fibrosis. Pediatric Research 40:4, 578-586
   CrossRef

7. 7

   Gregory L. Kearns, William R. Crom, Karl H. Karlson, George B. Mallory, William E. Evans. (1996) Hepatic drug clearance in patients with mild cystic fibrosis*. Clinical Pharmacology & Therapeutics 59:5, 529-540
   CrossRef

8. 8

   Gan, King-HanVeeze, Henk J.van den Ouweland, AnsHalley, DickyScheffer, Hansvan der Hout, AnnemiekeOverbeek, Shelley E.de Jongste, Johan C.Bakker, WillemHeijerman, Harry. (1995) A Cystic Fibrosis Mutation Associated with Mild Lung Disease. New England Journal of Medicine 333:2, 95-99
   Full Text