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A monogenetic disorder yet multiple and varied clinical manifestations
  1. L I Landau
  1. Correspondence to:
    Prof. L Landau
    Professor of Paediatrics, The University of Western Australia, Perth, Western Australia;

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Commentary on the paper by Callaghan et al (see page1029)

It was thought that identification of the cystic fibrosis gene—the cystic fibrosis transmembrane conductance regulator—15 years ago would lead to the solution for many of the serious consequences of this most common inherited fatal disorder. Instead, over 1000 mutations of this single gene have been reported with varied disease manifestations for each of these different mutations for cystic fibrosis. Substantial variations in the disease within the same CFTR genotype have been found. The impact of CFTR on other conditions such as infertility, diarrhoeal diseases (cholera), and asthma, has been described. This highlights the need for further investigation to better understand the mechanisms for the varied phenotypic expression of these numerous polymorphisms of CFTR.

In this issue, Callaghan and colleagues1 report on growth and lung function in Asian patients in the United Kingdom with cystic fibrosis. They found that Asian girls had lower FEV1 and FVC, but isolation of Pseudomonas aeruginosa at a later age (on average 3 years later) than a matched control group. These findings are different to those reported by Bowler et al from Leeds,2 who found that the Asian patients had lower respiratory function results, lower BMI (body mass index), and isolated P aeruginosa on average 3 years earlier than the control group.

These observations raise interesting issues that are essential to our understanding of the impact of the environment on phenotypic expression of most genetic disorders. Asians have a low incidence of cystic fibrosis and lower prevalence of the ΔF508 mutation.

Kabra and colleagues3 reported 17% prevalence of ΔF508 in cystic fibrosis children in India and Pakistan compared with over 70% in most Caucasian cystic fibrosis cohorts. Although diagnosis was delayed in these patients, the clinical presentation was otherwise described as classical. Wang and colleagues4 found no ΔF508 mutations in 100 Japanese children with cystic fibrosis. Just as the pattern of mutations varies throughout Caucasian societies, especially as one moves from the Mediterranean to Northern Europe, similar variations appear to be present in different Asian societies.

Wu and colleagues5 found that the frequency of CFTR mutant alleles in Taiwanese men with congenital bilateral absence of the vas deferens (CBAVD) was 36%, lower than published frequencies in other ethnic CBAVD patients (ranging from 50% to 74%).As well the mutation spectrum of CFTR in CBAVD patients did not overlap with the Caucasian CFTR mutation spectrum in this condition.

The environmental impact on phenotypic expression can relate to social factors such as recognition affecting the age of diagnosis, access to medical care, compliance with recommended care, and relative social disadvantage, especially in migrant communities.

Gene expression can be influenced more directly by epigenetic factors such as diet and toxins or by epigenetic inheritance of modifier genes co-inherited with the candidate gene. Promoter sequences elsewhere in the genes, independent of CFTR, may exert considerable influence on the outcomes of CF. However, a definitive modifier gene for CF remains to be identified.6 The expression of particular alleles in other conditions may also be influenced by whether the particular allele was inherited from the father or the mother and this may even be applicable to CF.7

The impact of gender of the affected child is clearly another important factor to consider as reported in the paper by Callaghan and colleagues.1 Kuhni and Sennhauser8 have reported that the Yentl syndrome is alive and well with under-diagnosis and under-treatment in Swiss girls with asthma. Gee and colleagues9 have found differences in attitude by children to their cystic fibrosis between girls and boys, with the girls’ perceptions relating better to test results but poorer with respect to body image.

Another important perspective to consider is the best descriptor and predictor of disease severity and outcome. Most reports analyse outcomes individually on lung function, somatic growth, or sputum culture results. Liou and colleagues10 have argued that a multivariate model including age, gender, BMI, lung function, pancreatic insufficiency, diabetes mellitus, sputum cultures, and number of acute exacerbations provides a rigorous tool for clinical practice and research. This type of model may well better help us define accurately the phenotype to assist in the investigation of the environmental and epigenetic factors that impact on the expression of the various polymorphisms of the CFTR. Identification of these factors can only lead to improvement in outcome by better targeting therapeutic interventions.

Commentary on the paper by Callaghan et al (see page1029)


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  • Competing interests: none declared

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