Variable Severity of Pulmonary Disease in Adults with Identical Cystic Fibrosis Mutations

doi:10.1378/chest.102.2.506

Chest

Volume 102, Issue 2, August 1992, Pages 506-509

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Adults with CF followed in a university center were assessed for the presence of the most common CF gene mutation, delta-F508. Excluding one member of a sibling pair, 29 of 55 subjects had two copies of delta-F508 (homozygotes), 23 had one copy of delta-F508 with the other CF mutation not identified (complex heterozygotes) and three were lacking delta-F508. A wide range of clinical severity was seen among individuals carrying two copies of the delta-F508 gene, who are genetically identical at the CF gene locus. The number of individuals diagnosed with CF as adults was significantly lower in the homozygote group (1 of 29) as compared with the heterozygote group (7 of 24). No differences were detected between groups in pulmonary function, non-pulmonary complications or overall clinical severity. These results suggest that environmental or background genetic factors contribute significantly to the variability in pulmonary and other complications seen among individuals with CF.

Section snippets

Subjects

Adults followed up in the University of Washington Medical Center Adult Cystic Fibrosis Clinic were offered the opportunity to have their delta-F508 status determined for genetic counseling. Results are shown for 56 patients out of a total of 64 CF adults actively followed up in this clinic. The sample of 56 subjects represents 67 percent of the known CF-affected adults (n = 84) living in western Washington. Genetic testing was done over an 18-month period from January 1990 to July 1991. Three

RESULTS

Of the 56 subjects tested, 29 were homozygous for the delta-F508 mutation. Twenty-four (including the sibling pair) had one copy of delta-F508 with the other CF mutation not identified (complex heterozygotes), and three subjects lacked the delta-F508 mutation. Thus, excluding one member of the sibling pair, 29 of 55 (53 percent) were homozygous for the delta-F508 mutation, 23 of 55 (42 percent) were heterozygous for the delta-F508 mutation and 3 of 55 (5 percent) lacked the delta-F508 mutation

DISCUSSION

In the adult CF population reported here, a broad range of clinical severity was seen, including individuals with normal and minimally impaired pulmonary function. An eighth of the population was more than 30 years of age. In this population, the frequency of the delta-F508 mutation was the same as seen in larger, unselected CF populations.6, 7

We found a higher percentage of adult diagnoses of CF among the complex heterozygote group (delta-F508/Other) than in the homozygous group

REFERENCES (12)

SuCT et al.
“Typical” cystic fibrosis in an elderly woman
Am J Med
(1989)
StuhrmannM et al.
Genotype analysis of cystic fibrosis patients in relation to pancreatic sufficiency
Lancet
(1990)
TaussigLM et al.
A new prognostic score and clinical evaluation system for cystic fibrosis
J Pediatr
(1973)
KnowlesMR et al.
Mild cystic fibrosis in a consanguinous family
Ann Intern Med
(1989)
TaussigL
Cystic fibrosis
(1984)
CoreyM et al.
Five to seven-year course of pulmonary function in cystic fibrosis
Am Rev Respir Dis
(1976)

There are more references available in the full text version of this article.

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This chapter discusses recent advances in the field using some common inherited autosomal recessive, autosomal dominant, and X-linked diseases as examples. In addition, some common mitochondrial, imprinting, and complex disorders and inherited cancers are reviewed. For each disease, information regarding the clinical phenotype, gene, protein function, treatment, and currently used clinical molecular diagnostic techniques are summarized.
Influence of SNPs in Genes that Modulate Lung Disease Severity in a Group of Mexican Patients with Cystic Fibrosis
2018, Archives of Medical Research
The variation in cystic fibrosis (CF) lung disease not always is explained by the CFTR genotype, so it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of CF, so we investigated the association of allelic variants in modifier genes that modulate the severity of lung function in a group of Mexican patients diagnosed with CF.
We included 140 CF patients classified according to lung phenotype and analyzed 17 single nucleotide polymorphisms (SNPs) by TaqMan^® allelic discrimination.
We demonstrated that patients with GG or GC genotype of the allelic variant rs11003125 (MBL2-550) of the MBL2 gene exhibit most of the lung manifestations at an earlier age; and the rs1042713 allelic variant of ADRB2 gene, showed statistical difference only with the age of first spirometry. When we used the dominant model, the MBL2 allele rs11003125 (MBL2-550; p = 0.022, Odds Ratio (OR) 2.87, 95% CI 1.14–7.27) was significantly associated with CF patients as risk factor, and the ADRB2 allele rs1042713 (p.Arg16Gly; p = 0.005, Odds Ratio (OR) 0.37, 95% CI 0.19–0.75) was significantly associated with CF patients as protect factor.
Our findings suggest that the MBL2 and ADRB2 genes exerts an important genetic influence on the lung disease in our patients. Taking into account our results, we insist on not leaving aside this type of studies, since having techniques such as GWAS or WES will be able to advance in achieving a better quality of life for CF patients with severe lung disease.
The relationship between sweat chloride levels and mortality in cystic fibrosis varies by individual genotype
2018, Journal of Cystic Fibrosis
Citation Excerpt :
Patients with genotypes in functional classes 1–3 almost always have pancreatic insufficiency, are at high risk for early lung function decline and have decreased survival compared to lower-risk genotypes (functional classes 4 & 5) [10]. Even among patients with identical CFTR genotypes, the severity of disease may vary widely between individuals [11]. Important outcomes in CF, such as morbidity and mortality, are largely driven by progression of pulmonary disease [12,13].
The association between CFTR genotype, sweat chloride and mortality has been inconsistent, but no previous analyses have examined the association stratified by individual genotypes.
To evaluate the genotype-specific association between sweat chloride and mortality.
The CFF Patient Registry was assessed and included all patients in the registry between 1996 and 2012 with at least one F508del allele. We excluded patients without a documented genotype or plausible sweat chloride level. The primary outcome was time to mortality during the observation period. We examined 15 genotypes using the three most prevalent alleles in each of 5 classes. We compared subgroups of sweat chloride using Kaplan-Meier curves, log-rank tests, and multivariable Cox PH models. The overall predictive value of sweat chloride on mortality was assessed using area under the receiver operating characteristic curves.
18,893 subjects met inclusion criteria. Sweat chloride distribution was similar across genotypes in patients with class 1 mutations, but was significantly different across genotypes in mutation classes 2–5. The R117H/F508del genotype patients demonstrated an association between sweat chloride and mortality (HR: 1.32 for every 10 mmol/L increase in sweat chloride [95% CI 1.12–1.54]. There were also significant associations in patients with F508del/F508del, I507del/F508del, G551D/F508del and 2789 + 5G → A/F508del genotypes, though the clinical relevance for these genotypes is unclear.
There is significant variability in sweat chloride distribution across CFTR class 2–5 genotypes. The relationship between sweat chloride and mortality varies by genotype with a relatively strong relationship in R117H/F508del patients.
Diagnosis of Adult Patients with Cystic Fibrosis
2016, Clinics in Chest Medicine
Citation Excerpt :
Although F508del is the most common allele in adult-diagnosed cohorts,2,11–13 these patients often have a genotype that includes 1 or more class IV to VI mutations or an unidentified genetic abnormality.2,12–18 In rare cases, a severe genotype, including homozygote F508del, is identified in a patient diagnosed as an adult,10,12,13,19 which likely reflects the contribution of a growing list of genetic modifiers of CF.20–24 Other genetic abnormalities of CFTR may contribute to the presentation of the milder phenotype, include the noncoding 5T allele of the polythymidine tract in intron 8 (IVS8),10,25 as well as large sequence deletions, duplications, and in-cis distribution of benign polymorphisms.26–28 Even with extensive sequencing of all exons and intron/exon junctions, only a single mutation is identified in more than a quarter of individuals with the diagnosis of mild or atypical CF.28 Even if 2 CFTR abnormalities have been identified, only a small percentage of the more than 1800 identified genetic changes have been rigorously confirmed as CF-causing mutations.29
42-year-old man with asthma symptoms and recurrent bronchitis
2015, Mayo Clinic Proceedings
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It is not surprising then that 7% of patients with CF are adults at the time of diagnosis,11 with the oldest patient with a new diagnosis in 2012 being 76 years of age. Because of the more than 1400 different gene mutations or polymorphisms noted so far in CF clinical manifestations, clinical presentations in CF diagnosed in adults vary significantly.1 In general, patients with late presentation of CF tend to have less severe disease and to live longer than age-matched peers.2,3
Differences in the pattern of structural abnormalities on CT scan in patients with cystic fibrosis and pancreatic sufficiency or insufficiency
2013, Chest
Cystic fibrosis (CF) genotypes characterized by pancreatic sufficiency (PS) are generally associated with milder disease vs genotypes characterized by pancreatic insufficiency (PI); however, the correlation between pancreatic status and type and severity of structural lung changes has not been studied. We aimed to evaluate differences in the severity and distribution of pulmonary manifestations of CF in patients with PS vs PI.
We retrospectively evaluated changes in individual lobes and the whole lung on chest CT scan with the modified Brody score. The study population included 84 (39 female, 45 male) patients with CF aged 4 to 68 years (mean, 20.5) treated from 2000 to 2010. Our institutional review board waived the requirement for informed consent. The severity of lung changes and distribution of pulmonary disease were compared by Student t test, nonparametric Pearson χ² test, or mixed-design analysis of variance for 28 patients with CF-PS and 56 with CF-PI. Correlations were evaluated with the Pearson (continuous variables) or Spearman ρ (nonparametric variables) tests. A linear regression model was used for multivariate analyses.
Compared with patients with CF-PS, those with CF-PI had more-severe lung disease (P = .001) with predominant upper lobe involvement (P = .002) and significant differences in Brody scores for bronchiectasis and bronchial wall thickening. Lung manifestations in patients with CF-PS did not show predominant involvement of any one area (P = .133).
In patients with CF-PI, structural lung changes are more severe with upper lobe predominance, prominent bronchiectasis, and bronchial wall thickening vs lower severity and more general distribution of changes in those with CF-PS.

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: Manuscript received January 2; revision accepted November 22.

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Chest

Clinical InvestigationsVariable Severity of Pulmonary Disease in Adults with Identical Cystic Fibrosis Mutations

Section snippets

Subjects

RESULTS

DISCUSSION

Am J Med

Lancet

J Pediatr

Mild cystic fibrosis in a consanguinous family

Ann Intern Med

Cystic fibrosis

Five to seven-year course of pulmonary function in cystic fibrosis

Am Rev Respir Dis

Clinical Investigations
Variable Severity of Pulmonary Disease in Adults with Identical Cystic Fibrosis Mutations