Newborn screening for type 1 diabetes using genome-based risk scores in the Early Check program

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that often presents in childhood and can lead to life-threatening complications such as diabetic ketoacidosis. Genetic risk scores (GRSs) offer an innovative approach to early identification of T1D risk, but their integration into newborn screening (NBS) has not been implemented at scale in the United States. We evaluated the feasibility of using whole-genome sequencing (WGS) of dried blood spot samples to calculate and return T1D GRSs within a real-world screening program. Early Check is a statewide voluntary NBS research program in North Carolina. Between September 2023 and June 2024, 2,125 newborns were enrolled for WGS-based screening, including optional GRS-based T1D screening. Predicted T1D risk was calculated using a validated pipeline based on the previously developed 67-variant T1D GRS2 model. Results were returned to parents via a secure portal, and newborns with elevated genetic risk were offered islet autoantibody testing. Of the 1,742 newborns whose parents elected T1D screening, 1,603 (92%) received a valid GRS2 result. Sixty-two (3.9%) were classified as higher concern and 118 (7.4%) as moderate concern. Among the higher-concern group, 41 initiated autoantibody testing at 9 months, with two testing positive; both reverted to negative at 12 months. GRS2 scores were lower in African ancestry newborns, highlighting the need for ancestry-specific thresholds or models. T1D GRS screening is feasible in a population NBS using WGS. Results support its potential for early-life risk stratification while underscoring the need for improved cross-ancestry performance and long-term validation.