Trisomy 21 is a Cause of Permanent Neonatal Diabetes that is Autoimmune but not HLA Associated

Abstract

Identifying new causes of permanent neonatal diabetes (diagnosis <6 months; PNDM) provides important insights into β-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are 4 times more likely to have childhood diabetes with an intermediate HLA association. It is not known if DS can cause PNDM. We found trisomy 21 was 7 times more likely in our PNDM cohort than in the population (13/1522 = 85/10,000 observed vs. 12.6/10,000 expected) and none of the 13 DS-PNDM cases had a mutation in the known PNDM genes which explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4/9 DS-PNDM patients but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes. We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental type 1 diabetes that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.