Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy

Area of Science:

• Medical Genetics
• Rare Diseases
• Population Health

Background:

• Cystic Fibrosis (CF) is a rare, autosomal recessive, multisystem disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene.
• Understanding CFTR mutation prevalence is crucial for developing effective genetic testing and targeted therapies.
• The Republic of North Macedonia lacked comprehensive CF genetic data.

Purpose of the Study:

• To characterize the spectrum of CFTR mutations in cystic fibrosis patients in North Macedonia.
• To develop a population-specific, cost-effective genetic testing strategy for CF.
• To lay the groundwork for personalized CF treatment approaches in the region.

Main Methods:

• Genetic analysis of 158 unrelated CF patients from the National CF Registry.
• Screening for common CFTR mutations, followed by analysis of additional variants and large deletions using commercial kits.
• Sanger sequencing or Next Generation Sequencing (NGS) for undetermined genotypes.

Main Results:

• The most common CFTR mutation, F508del (c.l521_1523del), was identified in 75.9% of patients.
• A total of 26 other pathogenic variants and three large deletions in the CFTR gene were found.
• Two novel CFTR variants, c.1070 C>T (p.Ala357Val) and c.2779_2788dup CTTGCTATGG (p.Gly930AlafsTer48), were identified.
• A targeted single base extension method was designed, achieving a 90.0% detection rate for CF mutations in this population.

Conclusions:

• The genetic landscape of CF in North Macedonia is characterized by a high prevalence of the F508del mutation.
• A tailored, cost-effective genetic testing approach can significantly improve CF diagnosis rates in the region.
• This study provides essential data for advancing personalized medicine for cystic fibrosis patients in North Macedonia.