Emerging data reveal higher-than-expected prevalence of cystic fibrosis (CF) among non-European populations worldwide including in the Indian subcontinent. Systematic analyses of the CFTR mutation profile, and genotype-phenotype correlations among people with CF from south, east, or northeast India have not been reported before. We wanted to identify CFTR mutations in people with CF, and highlight novel variants, selective phenotypic correlations, and regional variances within India. A retrospective study was conducted at Christian Medical College, Vellore, India (single tertiary referral hospital) from September 2010 to August 2022, involving 120 people with CF from (i) four south Indian states (Tamil Nadu, Andhra Pradesh, Kerala, Karnataka), (ii) in and nearby regions of West Bengal, India and (iii) Bangladesh. Comprehensive CFTR mutation analyses were done by Next-Generation Sequencing, and variants were categorized per American College of Medical Genetics guidelines and compared with validated Locus-specific databases. Demographic characteristics, mutation profile, novel mutations, selective phenotype correlations, and regional variances were assessed. In 120 people with CF, 55 CFTR variants were identified, including six novel variants. F508del was the predominant mutation, yet with a lower allele frequency than reported among European populations (27% versus 70%). Phenotypic correlations suggested high mutational pathogenicity causing severe multi-organ morbidity, and death in 27%. Milder variants associated with pancreatic sufficiency were also evident in 23% of people with CF. Statistically significant regional variances were noted in genotype frequency, and clinical phenotype among people with CF from the two regions. Hotspot exons and introns that could potentially help create targeted mutation panels were identified. The identification of 55 different CFTR variants among 120 people with CF describes the diversity of mutations noted in India, while also revealing the challenges that providers may encounter in timely diagnosis and treatment of CF. However, these single-centre data have specific limitations and cannot be generalised to all people with CF from India or to those of non-European origin. Our data on regional CFTR mutations contribute to the emerging national registry on CF epidemiology in India, help formulate diagnostic and newborn screening algorithms, help optimise clinical care, and highlight urgency to improve access to life-changing modulator therapy. 10.13039/100000897 Cystic Fibrosis Foundation , USA (towards the CF-India Demonstration Project) and 10.13039/501100005918 Christian Medical College, Vellore , India.

Because a delayed diagnosis of cystic fibrosis (CF) is detrimental and may be fatal, screening at birth has become routine in the Western world and has proven beneficial for many reasons, in addition to enabling prompt specialized care. Newborn screening (NBS) programs have elucidated the true incidence of CF in a variety of populations and enabled rapid genotype identification through the analysis of the cystic fibrosis transmembrane regulator (CFTR) gene. NBS studies also have revealed regional and population differences in CFTR variants and refuted the dogma that CF is a “white person’s disease”. But some regions have not yet implemented CF NBS, particularly in Asia where the disease prevalence has been uncertain. While the needs of a few low-and-middle-income countries are being addressed sequentially, one of the regions of greatest current interest is the Indian subcontinent because of recent data suggesting a higher incidence than that previously assumed, and clinical observations indicating tragic outcomes due to delayed diagnoses or failure to diagnose the disorder in young children. Thus, we conclude that the opportunities for research combined with service in the Indian subcontinent are urgent and potentially very impactful. Consequently, India is the last and best frontier for CF NBS, as we argue herein.