Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Abstract

Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into β-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). 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 T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.

Figure 1

DS is enriched in our PNDM cohort. DS has a population prevalence of 12.6 of 10,000 (95% CI 12.4–12.8), whereas in our cohort of 1,522 patients with neonatal diabetes we have 13 cases, equivalent to 85 of 10,000 (40.4–144.3); P = 0.007.

Figure 2

DS-PNDM is not caused by other known neonatal diabetes genes. The 24 known neonatal diabetes genes account for 82.9% of cases, while none of the 13 DS-PNDM case subjects had a mutation in a known gene (P = 1.4 × 10⁻¹⁰).

Figure 3

The T1D-GRS in DS-PNDM. Patients with DS-PNDM (n = 13) had a lower score than T1D control subjects (n = 1,963), and their scores were similar to those with the known monogenic forms of non-DS PNDM and autoimmune non-DS PNDM (n = 458 and n = 40, respectively; P = 0.52) and control subjects without diabetes (n = 2,938; P = 0.33). The central line within the box represents the median, and the upper and lower limits of the box represent the interquartile range. The whiskers are the most extreme values within 1.5× the interquartile range from the first and second quartiles.