BACKGROUND While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology is not studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. METHODS We conducted a multicentre, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2 and zinc transporter 8, using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. RESULTS Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous, and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8 and PTF1A loci were detected. CONCLUSIONS Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM.

中文翻译：

---

印度胰岛抗体阴性 1 型糖尿病儿童中隐性 WFS1 突变的发生率较高。

背景虽然据报道印度儿童中胰岛抗体阴性（特发性）1 型糖尿病（T1DM）的发病率有所增加，但其病因学尚未研究。我们研究了单基因糖尿病在胰岛抗体阴性 T1DM 病因中的作用。方法 我们对 169 名新发 T1DM 的印度儿童（1-18 岁）进行了一项多中心、前瞻性、观察性研究。使用经过验证的 ELISA，对所有样本进行了针对 GAD65、胰岛抗原 2 和锌转运蛋白 8 的抗体测试。使用 Illumina 平台对 34 名胰岛抗体阴性儿童进行了与单基因糖尿病有关的 31 个基因的靶向下一代测序。所有突变均通过桑格测序证实。结果 三十五名 (21%) 儿童的所有胰岛抗体均为阴性。12 名患者（占整个队列的 7%，胰岛抗体阴性 T1DM 患者中的 34%）被检测出具有致病性或可能致病性遗传变异。最常受影响的位点是 WFS1，有 9 名患者（占整个队列的 5%，胰岛抗体阴性的 26%）。其中包括 7 名纯合子儿童和 1 名患者，各有复合杂合子和杂合子突变。Wolfram 综合征 1 (WS) 儿童表现为严重的胰岛素需求型糖尿病（包括 3 名酮症酸中毒患者），但未检测到其他综合征表现。在 3 名患者中，检测到 HNF4A、ABCC8 和 PTF1A 基因座的杂合突变。结论 近四分之一的胰岛抗体阴性 T1DM 印度儿童存在 WFS1 基因隐性突变。这些患者在诊断时没有表现出 WS 的其他特征。对于抗体阴性 T1DM 的印度儿童，应考虑进行单基因糖尿病检测，尤其是 WS。