Profile of cystic fibrosis transmembrane conductance regulator (CFTR) gene variants across India and their variability in different geographic regions.

Cystic Fibrosis (CF) is increasingly diagnosed in non-European populations, including Indian children, with wide regional and ethnic variation in CFTR genotypic spectrum. This study aimed to document the CFTR genetic profile in Indian children and assess regional variability. In a multicentric effort to strengthen CF services in India, data were collected from children with confirmed CF at AIIMS New Delhi, SKIMS Srinagar, AIIMS Jodhpur, and CMC Vellore. A stepwise testing strategy was used: initial screening for two common variants via Sanger sequencing and RFLP, followed by NGS and MLPA for broader variant detection. Among 260 children (520chromosomes), 105 CFTR variants were identified. The most common variant, p.Phe508del, had an allele frequency of 29-34% across regions-substantially lower than the 70-80% seen in Europeans. Each region showed 4-5 common variants. The genotypic spectrum in southern/eastern India resembled that of West/Southwest Asia, while northern/western India showed similarity to Western Europe. Fourteen novel variants were detected: seven pathogenic, three likely pathogenic, and four of uncertain significance. This is one of the most comprehensive studies to reveal region-specific CFTR variants in India. The lower prevalence of p.Phe508del and distinct genotypic patterns across regions highlight the need for customized diagnostic algorithm. There is an urgent need to evaluate the efficacy of current CFTR modulators and to explore the development of new treatments based on the unique Indian molecular spectrum.