Opportunistic analysis of clinically actionable DPYD gene variants in a germline testing cohort in India

Dihydropyrimidine dehydrogenase (DPYD) plays a critical role in the metabolism of fluoropyrimidine-based chemotherapies such as 5-fluorouracil (5-FU), capecitabine, and tegafur. Genetic variants in DPYD can lead to partial or complete enzyme deficiency, resulting in toxic accumulation of these drugs and severe, sometimes fatal, adverse reactions.

Whole‑exome sequencing data from 1,612 individuals were analyzed for DPYD variants. Variants were classified as decreased, no function, or potentially deleterious. Comparative allele frequency analysis was performed using global population datasets to identify inter-population differences.

A total of 95 individuals (5.3%) carried at least one decreased or no function DPYD variant, indicating a significant prevalence of clinically actionable genotypes in this Indian cohort. The most frequent variant, c.1236 G > A (HapB3), was found in 53 individuals (3.28%), supporting its relevance in the Indian population. Comparative analysis revealed distinct population patterns and novel variants not captured in current guidelines. These results support the urgency in implementing preemptive DPYD genotyping to avoid adverse drug reactions and further studies to gather evidence on rare and novel variants in the Indian population. To the best of our knowledge, this is the largest population analysis of DPYD variants from India.