Donis Russell, Patel Kashyap A, Wakeling Matthew N, Johnson Matthew B, Amoli Masha M, Yildiz Melek, Akçay Teoman, Aspi Irani, Yong James, Yaghootkar Hanieh, Weedon Michael N, Hattersley Andrew T, Flanagan Sarah E, De Franco Elisa
Department of Clinical and Biomedical Science, University of Exeter Faculty of Health and Life Sciences, Exeter, UK.
Metabolic Disorders Research Centre, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
Diabet Med. 2025 Mar;42(3):e15471. doi: 10.1111/dme.15471. Epub 2024 Nov 7.
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.
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.
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.
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.
新生儿糖尿病是一种单基因疾病，可能是复杂综合征的首发症状。本研究的目的是确定具有神经学特征（包括发育迟缓与癫痫）的新生儿糖尿病的新遗传病因。
我们对27例患有新生儿糖尿病合并癫痫和/或不明遗传病因的发育迟缓患者进行了全基因组测序。采用靶向二代测序技术，对123例年龄≤1岁且无已知遗传病因的糖尿病患者进行了重复研究。
三名患者均在出生第一周被诊断为糖尿病，他们在TARS2基因中共享一个罕见的纯合错义变异p.(Arg327Gln)。重复研究在第四名1岁时被诊断为糖尿病的个体中发现了相同的纯合变异。一名先证者患有癫痫，一名患有发育迟缓，两名同时患有这两种疾病。双等位基因TARS2变异导致一种线粒体脑病（COXPD - 21），其特征为严重肌张力减退、癫痫和发育迟缓。糖尿病并非COXPD - 21的已知特征。目前的证据表明，p.(Arg327Gln)变异破坏了TARS2对mTORC1通路的调控，而该通路对β细胞至关重要。
我们的研究结果确定了纯合p.(Arg327Gln) TARS2变异是综合征性新生儿糖尿病的新病因，并揭示了TARS2在胰腺β细胞中的作用。
