Analysis of the genotypic profile and its relationship with the clinical manifestations in people with cystic fibrosis: study from a rare disease registry

Abstract

Background Cystic fibrosis (CF) has a vast and heterogeneous mutational spectrum in Europe. This variability has also been described in Spain, and there are numerous studies linking CFTR variants with the symptoms of the disease. Most of the studies analysed determinate clinical manifestations or specific sequence variants in patients from clinical units. Others used registry data without addressing the genotype–phenotype relationship. Therefore, the objective of this study is to describe the genetic and clinical characteristics of people with CF and to analyse the relationship between both using data from the rare disease registry of a region in southeastern Spain. Methods A cross-sectional study was carried out in people with a confirmed diagnosis of CF registered in the Rare Diseases Information System (SIER) of the Region of Murcia (Spain). The patients were classified into two genotypes according to the functional consequence that the genetic variants had on the CFTR protein. Results There were 192 people diagnosed with CF reported in the Region of Murcia as of 31 December 2018. Seventy-six genotypes and 49 different variants were described, with c.1521_1523delCTT (p. Phe508del) being the most common in 58.3% of the CF patients and 37.0% of the alleles. In addition, 67% of the patients were classified as a high-risk genotype, which was associated with a lower percentage of FEV1 (OR: 5.3; 95% CI: 1.2, 24.4), an increased risk of colonization by Pseudomonas aeruginosa (OR: 7.5; 95% CI: 1.7, 33.0) and the presence of pancreatic insufficiency (OR: 28.1; 95% CI: 9.3, 84.4) compared to those with a low-risk genotype. Conclusions This is the first study in Spain that describes the mutational spectrum and its association with clinical manifestations in patients with CF using data from a rare disease registry. The results obtained allow planning for the health resources needed by people with this disease, thus contributing to the development of personalized medicine that helps to optimize health care in CF patients.

Predictive factors of survival in people with cystic fibrosis from a Spanish rare disease registry.

“…However, in the genotype-adjusted model, only this and the development of CF-related liver disease and bone abnormalities were independent predictors of mortality and transplantation. These data are consistent with a previous study in which an association was found between the high-risk genotype and the most severe symptoms 24 .…”

“…Furthermore, the genotype has been reported as one of the most determining factors both in the phenotype and in the survival of people with CF 32 . The Region of Murcia is one of the regions that has described a lower allelic frequency of the p. Phe508del variant both at the national and European level and with a high percentage of heterozygous forms 24,33 . This fact may explain to a large extent because 33% of patients for whom genetic information was available have low-risk genotypes that have been associated with higher survival.…”

“…Those people in whom both alleles carried "minimal function variants" (class I, II, III and VII) were classi ed as "high-risk genotype". On the other hand, those in which at least one allele carried a "residual function variant" (class IV, V, and VI) were classi ed as a "low-risk genotype", with some previously described exceptions 24 .…”

“…The demographic, clinical and genotypic information registered in SIERrm was gathered for each patient individually. In a previous paper, the sources that provide information to the SIERrm are described, as well as the process of incorporating and validating these data into the registry 24 .…”

Should atelectasis be considered a pulmonary complication and indicator of poor prognosis in cystic fibrosis?

“…When considering certain genetic mutations related to more severe disease, there were no differences between the two study groups. 36,37 In our genetic study, the predominant mutation in the patients who presented with atelectasis was the heterozygous F508del (p.Phe508del) mutation (54.5%), followed by the homozygous F508del mutation (21.8%), which were almost identical to the findings in the latest European registry. 32 No relationship has been observed between genotype and pulmonary complications, possibly because the genotype–phenotype correlation is weaker for lung disease than for other comorbidities, although there are no specific studies for lung atelectasis, excluding our study.…”