Genotype-phenotype correlation in siblings with cystic fibrosis

Abstract

Introduction. Despite the genetic counseling, families with cystic fibrosis (CF) patients and modern possibilities of prenatal molecular genetic screening, the occurrence of CF in more than one child in a family is not rare. The same genotype is expected to determine the specific phenotype in CF patients, especially in siblings. However, broad clinical heterogeneity could indicate the influence of secondary genetic factors on the course of the disease. The aim of the study is to examine the genotype-phenotype correlation and disease course features in CF siblings, including twins. Materials and methods. A clinical retrospective cohort observational study included fifty three sibs (23 boys, 30 girls) aged from 6 months to 17 years 9 months (median age of 8.3 (4.8–12.9) years, age difference 5 ± 2 years) with a diagnosis of CF confirmed by molecular genetic methods. Group 1 consisted of 9 twin pairs (3 — monozygotic, 6 — dizygotic), group 2 — 35 complete sibs. Results. The mean age of diagnosis for older sibs is 2.5 years (8 months — 9,8 years; min — 1 months, max — 17 years) and for younger sibs — 8.5 months (1.3 months–3 years). Chronologically, the onset of CF was registered earlier in younger sibs than in older sibs in 3 (16.7%). In 6 (22.2%) of families, the pancreatic status of sibs varied from normal function to severe pancreatic insufficiency, with the occurrence of pancreatitis observed in only 4 (7.6%) patients. In 21 (77.8%) families with sibs infected by P.aeruginosa, 5 (23.8%) had a simultaneous primary culture of the pathogen, 8 (38,1%) had culture in both children but with an interval from 1 month to 9.5 years (Ме: 3.2 (5 months–4.9 years), and in 8 (38.1%) had culture in only 1 sibling. All younger sibs had the primary contamination at an earlier age with a 5.3 year (2–6.6 years;) difference. In 10 (37.0%) of the families, the pulmonary function of the sibs was variable. The number of bronchopulmonary exacerbations per year ranged in 8 (29.6%) of sib pairs and averaged 1.3 ± 0.5 in older sibs, 1.1 ± 0.3 in younger sibs, and 1.7 ± 1.3 in twins. The severity of hepatic involvement varied in 9 (33.3%) of sib pairs: no morbidity in 6 (33.3%), cystic fibrosis-associated fibrosis in 7 (38.9%), and cirrhosis with portal hypertension in 5 (27.8%). Conclusion. CF siblings, despite the same genotype, similar environmental conditions, and high risk of cross-infection, are characterized by wide phenotypic heterogeneity. Aside from the pathogenic CFTR variants, there are other genetic (modifier genes) and epigenetic (microRNA, DNA methylation) factors that could contribute to the clinical features of cystic fibrosis.