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Genotype-phenotype correlations in cystic fibrosis: clinical severity of mutation S549R(T-->G)
P M Frossard1, J Hertecant, Y Bossaert
1Dept of Pathology, Faculty of Medicine & Health Sciences, Tawam Hospital, Al Ain, United Arab Emirates.
Insights
Cystic fibrosis (CF) patients in the UAE homozygous for the CFTR S549R(T-->G) mutation exhibit a severe and homogeneous clinical presentation. This genotype is linked to early diagnosis, pancreatic insufficiency, and aggressive lung disease.
Area of Science:
- Genetics
- Pediatrics
- Pulmonology
Background:
- Cystic Fibrosis (CF) is a genetic disorder affecting multiple organs.
- Understanding genotype-phenotype correlations is crucial for CF management.
- The CFTR S549R(T-->G) mutation was previously considered private.
Purpose of the Study:
- To investigate the genotype-to-phenotype correlation in UAE children with CF.
- To characterize the clinical presentation of CF patients homozygous for the CFTR S549R(T-->G) mutation.
Main Methods:
- Retrospective analysis of 15 CF children (9 female, 6 male) in the UAE.
- Examined genotype (CFTR S549R(T-->G) homozygosity) against 20 clinical outcome variables.
- Included age at diagnosis, sweat chloride, growth, meconium ileus, pancreatic function, lung disease, complications, and microbial colonization.
Main Results:
- Mean age and age at diagnosis were low (5.4 and 1.0 years, respectively).
- All patients had pancreatic insufficiency and severe lung disease, with high rates of Pseudomonas aeruginosa and Staphylococcus aureus colonization.
- No patients presented with meconium ileus; two died during the study (at 5 months and 6 years).
Conclusions:
- The CFTR S549R(T-->G) homozygous genotype in UAE CF patients presents a homogeneous and severe phenotype.
- This mutation is associated with early-onset, severe cystic fibrosis with significant pulmonary involvement.
- Findings highlight the extreme severity and course of CF in this specific patient cohort.
Abstract:
With a view to assessing genotype-to-phenotype correlations in cystic fibrosis (CF), the clinical presentation of CF children from the United Arab Emirates (UAE) who were homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutation S549R(T-->G was investigated. This mutation is localized in intron 11 (nucleotide binding domain 1 of the CFTR protein) and had so far been described as a private mutation only. The associations between the R549/R549 genotype and 20 outcome variables, including age at diagnosis, sweat chloride concentrations, growth percentiles, meconium ileus, pancreatic sufficiency, pulmonary disease, associated complications and micro-organism colonization were examined in a group of 15 CF children (9 females and 6 males). Mean current age and age at diagnosis were both low (5.4+/-3.5 and 1.0+/-1.1 yrs, respectively). Although none of the 15 CF patients had presented with meconium ileus at birth, all were pancreatic insufficient and had very severe lung disease, with a high rate of Pseudomonas aeruginosa and Staphylococcus aureus. Two patients died during the course of this investigation (one was 5 months and the other, 6 yrs old). The clinical presentation associated with S549R(T-->G) homozygosity in the United Arab Emirates is quite homogeneous and shows an extreme degree and course of cystic fibrosis severity.
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