Abstract
Aims/hypothesisDiabetes diagnosed at <6 months of age is usually monogenic. However, 10–15% of affected infants do not have a pathogenic variant in one of the 26 known neonatal diabetes genes. We characterised infants diagnosed at <6 months of age without a pathogenic variant to assess whether polygenic type 1 diabetes could arise at early ages.MethodsWe studied 166 infants diagnosed with type 1 diabetes at <6 months of age in whom pathogenic variants in all 26 known genes had been excluded and compared them with infants with monogenic neonatal diabetes (n = 164) or children with type 1 diabetes diagnosed at 6–24 months of age (n = 152). We assessed the type 1 diabetes genetic risk score (T1D-GRS), islet autoantibodies, C-peptide and clinical features.ResultsWe found an excess of infants with high T1D-GRS: 38% (63/166) had a T1D-GRS >95th centile of healthy individuals, whereas 5% (8/166) would be expected if all were monogenic (p < 0.0001). Individuals with a high T1D-GRS had a similar rate of autoantibody positivity to that seen in individuals with type 1 diabetes diagnosed at 6–24 months of age (41% vs 58%, p = 0.2), and had markedly reduced C-peptide levels (median <3 pmol/l within 1 year of diagnosis), reflecting rapid loss of insulin secretion. These individuals also had reduced birthweights (median z score −0.89), which were lowest in those diagnosed with type 1 diabetes at <3 months of age (median z score −1.98).Conclusions/interpretationWe provide strong evidence that type 1 diabetes can present before the age of 6 months based on individuals with this extremely early-onset diabetes subtype having the classic features of childhood type 1 diabetes: high genetic risk, autoimmunity and rapid beta cell loss. The early-onset association with reduced birthweight raises the possibility that for some individuals there was reduced insulin secretion in utero. Comprehensive genetic testing for all neonatal diabetes genes remains essential for all individuals diagnosed with diabetes at <6 months of age.Graphical abstract
Highlights
Diabetes that presents in the first 6 months of life has been thought to be exclusively caused by a pathogenic variant in a single gene; nearly 90% of individuals have one of 26 known causes depending on cohort definition, highlighting the need for comprehensive genetic testing [1,2,3,4,5,6].Diabetologia (2020) 63:2605–2615The remaining ~10–15% may have a causative pathogenic variant in a gene or non-coding region that has not yet been identified
We showed that a type 1 diabetes genetic risk score (T1D-GRS), which expresses genetic risk as a continuum, could be used to discriminate type 1 diabetes from monogenic diabetes including neonatal diabetes (NDM)
Individuals with diabetes of unknown genetic aetiology diagnosed before 6 months of age We studied 166/1438 (12%) individuals referred to our laboratory for genetic testing for permanent NDM between 2000 and 2019 in whom comprehensive targeted next-generation sequencing had excluded a pathogenic variant in the 26 known genes
Summary
The remaining ~10–15% may have a causative pathogenic variant in a gene or non-coding region that has not yet been identified. Another possibility is that they have polygenic type 1 diabetes and represent the extreme tail of the distribution of presenting age of type 1 diabetes [7]. There are rare examples of autoimmune diseases, including autoimmune diabetes, presenting before the age of 6 months but these are caused either by highly penetrant pathogenic variants in immune genes such as FOXP3, STAT3 and LRBA [2, 3, 12] or, as for neonatal lupus, by passive transfer of pathogenic maternal antibodies [13]. No polygenic autoimmune diseases (including type 1 diabetes) have been described and characterised in individuals below the age of 6 months
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