Sickle cell disease (SCD) is one of the most prevalent autosomal recessive conditions worldwide, affecting more than 600,000 newborns annually. Despite advances in treatment, it remains a chronic condition requiring lifelong management. Allogeneic transplantation and gene therapy are currently the only curative options when applicable and available. We present the results of a pilot study evaluating the use of digital PCR (dPCR) for non-invasive prenatal diagnosis (NIPD), a minimally invasive approach for SCD, based on relative pathogenic variant dosage (RMD, Relative Mutation Dosage) analysis in maternal plasma. Nine pregnant women carrying the pathogenic variant (βA/βS) were included. RMD values ranged from 0.436 to 0.501 (mean: 0.475) in cases with heterozygous fetuses and from 0.377 to 0.431 (mean: 0.397) in cases with wild-type fetuses. Z-score classification correctly identified fetal genotype in all conclusive cases (8/9), with one inconclusive result. Results were confirmed postnatally with 100% concordance in classified cases. These findings support the feasibility of dPCR-based NIPD for SCD as a minimally invasive approach. However, further validation in larger cohorts and with comprehensive quality control parameters is required.
