A Homozygous Tars2 Variant Is a Novel Cause of Syndromic Neonatal Diabetes Publisher Pubmed



Donis R¹ ; Patel KA¹ ; Wakeling MN¹ ; Johnson MB¹ ; Amoli MM² ; Yildiz M³ ; Akcay T⁴ ; Aspi I^{5, 6} ; Yong J⁷ ; Yaghootkar H⁸ ; Weedon MN¹ ; Hattersley AT¹ ; Flanagan SE¹ ; De Franco E¹ Show Affiliations
Source: Diabetic Medicine Published:2025

Abstract

Aims: Neonatal diabetes is a monogenic condition which can be the presenting feature of complex syndromes. The aim of this study was to identify novel genetic causes of neonatal diabetes with neurological features including developmental delay and epilepsy. Methods: We performed genome sequencing in 27 individuals with neonatal diabetes plus epilepsy and/or developmental delay of unknown genetic cause. Replication studies were performed in 123 individuals with diabetes diagnosed aged ≤1 year without a known genetic cause using targeted next-generation sequencing. Results: Three individuals, all diagnosed with diabetes in the first week of life, shared a rare homozygous missense variant, p.(Arg327Gln), in TARS2. Replication studies identified the same homozygous variant in a fourth individual diagnosed with diabetes at 1 year. One proband had epilepsy, one had development delay and two had both. Biallelic TARS2 variants cause a mitochondrial encephalopathy (COXPD-21) characterised by severe hypotonia, epilepsy and developmental delay. Diabetes is not a known feature of COXPD-21. Current evidence suggests that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for β-cells. Conclusions: Our findings establish the homozygous p.(Arg327Gln) TARS2 variant as a novel cause of syndromic neonatal diabetes and uncover a role for TARS2 in pancreatic β-cells. © 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.