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160/200) Identifying new causes of permanent neonatal diabetes (diagnosis <6 months; PNDM) provides important insights into -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. Permanent neonatal diabetes (PNDM) is diagnosed before the age of 6 months and a genetic diagnosis is possible for >82% of cases (1). Twenty-four causative PNDM genes have been identified (1–4) and 4 of these cause monogenic autoimmune PNDM that results from destruction of the β-cells very early in life (FOXP3, IL2RA, LRBA and STAT3). Identifying novel causes of autoimmune neonatal diabetes can provide key insights into the development of autoimmunity and can provide new targets for therapeutic intervention. Down syndrome (DS) is caused by trisomy of chromosome 21 and has an incidence of 1:700 to 1:1100 live births (5). Large studies have shown childhood-onset autoimmune diabetes is 4 times more common in DS than in the general population, and has an intermediate HLA association (6). There have been three reported cases of DS with diabetes diagnosed before 6 months (7,8). However, it is not known whether DS was the cause of PNDM (DS-PNDM) or a coincidental finding in these patients. The aim of our study was to use our large international cohort of PNDM patients to assess whether DS can aetiologically cause PNDM. We assessed clinical phenotype, islet autoantibodies, and polygenic risk of T1D in patients with monogenic PNDM and DS-PNDM.

Trisomy 21 is a cause of permanent neonatal diabetes that is autoimmune but not HLA associated