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

Area of Science:

• Genetics
• Pediatrics
• Autoimmune Diseases

Background:

• Type 1 diabetes (T1D) is a significant childhood autoimmune disease with severe complications.
• Genetic risk scores (GRSs) show promise for early T1D risk identification.
• Integrating GRSs into newborn screening (NBS) remains largely unaddressed in the US.

Purpose of the Study:

• To assess the feasibility of using whole-genome sequencing (WGS) for calculating and returning T1D GRSs within a real-world NBS program.
• To evaluate the utility of T1D GRSs for early risk stratification in newborns.
• To identify challenges and areas for improvement in population-based GRS screening.

Main Methods:

• Whole-genome sequencing (WGS) was performed on dried blood spot samples from newborns in a voluntary NBS research program (Early Check, North Carolina).
• A validated 67-variant T1D GRS2 model was used to calculate predicted T1D risk.
• Results were returned to parents, and newborns with elevated genetic risk were offered islet autoantibody testing.

Main Results:

• Of 1,742 newborns with elected T1D screening, 92% received a valid GRS2 result.
• 3.9% were classified as higher concern and 7.4% as moderate concern for T1D risk.
• In the higher-concern group, 2 out of 41 infants tested positive for autoantibodies, but both reverted to negative by 12 months.
• Lower GRS2 scores were observed in African ancestry newborns, indicating a need for ancestry-specific models.

Conclusions:

• Population-based T1D GRS screening using WGS is feasible within an NBS framework.
• GRS screening supports early-life risk stratification for T1D.
• Further research is needed to improve cross-ancestry performance and conduct long-term validation of T1D GRS screening.