IDENTIFYING THE CFTR PATHOGENIC VARIANTS THROUGH NEXT GENERATION SEQUENCING IN BRAZILIAN CHILDREN WITH CYSTIC FIBROSIS
Next generation sequencing; CFTR gene; rare variants; phenotypes profile
Objective: To identify the spectrum of CFTR pathogenic variants in cystic fibrosis (CF) patients and to describe their phenotypic-genotypic features. We also sought to introduce as a routine evaluation to expose a possible rare mutation not described yet in CF databases.
Study design: We recruited 31 patients aged 1-37 years who had no molecular genetic diagnosis to perform CFTR mutation analysis through next-generation sequencing (NGS) and to detect new nucleotide variations. We associated clinical and diagnostic data with genetic testing to introduce as a routine evaluation.
Results: Mean age at diagnosis was 4 ± 4.4 years, although 26 (83.8%) started symptoms at 7-month-old. Eight (25.8%) were consanguineous. Thirteen (41,9%) had inadequate anthropometry at diagnosis. Twenty-three (74.2%) already had Pseudomonas aeruginosa (PA) in initial sputum cytobacteriological. NGS confirmed diagnosis in 29 (93.5%) patients. The mutational analysis resulted in 23 (74.1%) patients with p.Phe508del - 18 p.Phe508del homozygous and 5 heterozygous. Seven other rare variants were found: p.Ser4*, p.Trp1282*, c.2989-3C>G, p.Trp1089*, p.Ser364Metfs*7, p.Gly542*, p.Gln685Thrfs.
Conclusion: NGS technology allowed the recognition of p.Phe508del as the most common mutation, which causes a more severe CF phenotype. Besides, NGS disclosed a variant never described before related to its protein CFTR change, the p.Ser364Metfs*7. This technique could be introduced as a routine evaluation soon after the altered IRT e/or SCT to classify patients to new modulators therapies and better management of our actual and future CF patients.