Targeted analysis of whole exome sequencing in Thai patients with neonatal diabetes

TL;DR

This study identifies genetic causes of neonatal diabetes in Thai patients using whole exome sequencing, revealing new insights into the condition's genetic diversity in this population.

Contribution

The first genetic analysis of neonatal diabetes in Thai patients, highlighting novel pathogenic variants and successful precision therapy outcomes.

Findings

Eight out of 14 Thai NDM patients had variants in established NDM genes like KCNJ11, ABCC8, and INS.

Two patients with KCNJ11 variants achieved excellent glycemic control using sulfonylureas.

Six patients had pathogenic variants in genes linked to monogenic diabetes, including LRBA, EIF2AK3, and WFS1.

Abstract

Neonatal diabetes mellitus (NDM) typically presents within the first 6 months of life and generally lacks islet autoantibodies. Genetic elucidation of NDM is a prime example of precision medicine in diabetes. However, no published genetic data exist for NDM in Thailand. We aimed to assess the genetic etiology of Thai NDM using whole exome sequencing (WES). We enrolled 14 Thai patients with NDM and measured GAD65, IA-2, and ZnT8 autoantibodies. We then performed WES and analyzed 43 NDM-related genes to identify causative variants. All subjects tested negative for the three islet autoantibodies. Eight harbored variants in well-established NDM genes (KCNJ11 [n = 5], ABCC8 [n = 1], INS [n = 2 in identical twins]). Two patients with KCNJ11 variants (rs80356616: p.Val59Met and rs8035661: p.Arg50Gln) achieved excellent glycemic control on sulfonylureas, illustrating precision therapy. The remaining six carried pathogenic variants in genes associated with monogenic diabetes, including LRBA, EIF2AK3, DOCK8, WFS1, GATA6, CISD2/SLC9B1, and COQ2. This is the first report on the genetic etiology of NDM in Thailand. WES is an effective approach to identifying variants in this rare diabetes subtype. Larger cohort studies are needed to determine the true prevalence of NDM in Thailand.

The online version contains supplementary material available at 10.1007/s00439-025-02815-0.

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