Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity

Abstract

Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a β-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.

Keywords: MODY; early-onset; type 1 diabetes; whole exome sequencing; β-cell dysfunction.

Figure 1

T1D-GRS is similar in EOT1D children regardless of the presence of rare variants in MODY genes. (a) Boxplot of T1D-GRS from 171 healthy controls (Ctr), 91 EOT1D children without deleterious rare variants in MODY genes, and 8 EOT1D children with potentially deleterious MODY rare variants. The central line within the box represents the median, and the upper and lower limits of the box represent the IQR (interquartile range). Lower and upper whiskers cover the lowest and highest 25% of data, respectively. The horizontal line shows a GRS equivalent to the 5th percentile for the control group, used to divide T1D children into high GRS (above the 5th percentile) and low GRS (below the 5th percentile). Mann–Whitney test was used for comparison between groups (^∗∗∗∗p < 1 × 10⁻⁴). (b) ROC curve (area under the curve 0.9125) for T1D-GRS to discriminate EOT1D children without deleterious MODY rare variants (n = 91) from controls (n = 171).