Bhattacharya Saptarshi, Fernandez Cornelius J, Kamrul-Hasan Abul Bashar Mohammad, Pappachan Joseph M
Department of Endocrinology, Indraprastha Apollo Hospitals, Delhi 110076, India.
Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom.
World J Diabetes. 2025 May 15;16(5):104787. doi: 10.4239/wjd.v16.i5.104787.
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene. Maturity-onset diabetes of the young (MODY) is the most common type with 14 subtypes, each linked to specific mutations affecting insulin synthesis, secretion and glucose regulation. Common traits across MODY subtypes include early-onset diabetes, a family history of autosomal dominant diabetes, lack of features of insulin resistance, and absent islet cell autoimmunity. Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus. Biomarkers and scoring systems can help identify candidates for genetic testing. -MODY, a common subtype, manifests as mild hyperglycemia and doesn't require treatment except during pregnancy. In contrast, mutations in , and genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus. Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that usually presents within the first six months. Half of the cases are lifelong, while others experience transient remission. Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel ( or ) and can be transitioned to sulfonylurea after confirmation of diagnosis. Thus, in many cases, monogenic diabetes offers an opportunity to provide precision treatment. The scope has broadened with next-generation sequencing (NGS) technologies, replacing older methods like Sanger sequencing. NGS can be for targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing. Targeted gene panels offer specific information efficiently, while WES provides comprehensive data but comes with bioinformatic challenges. The surge in testing has also led to an increase in variants of unknown significance (VUS). Deciding whether VUS is disease-causing or benign can be challenging. Computational models, functional studies, and clinical knowledge help to determine pathogenicity. Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
单基因糖尿病是一种异质性疾病，其特征是由单个基因缺陷导致高血糖。青少年发病的成年型糖尿病（MODY）是最常见的类型，有14个亚型，每个亚型都与影响胰岛素合成、分泌和葡萄糖调节的特定突变有关。MODY亚型的共同特征包括早发性糖尿病、常染色体显性糖尿病家族史、缺乏胰岛素抵抗特征以及不存在胰岛细胞自身免疫。许多病例被误诊为1型和2型糖尿病。生物标志物和评分系统有助于确定基因检测的候选对象。常见的亚型MODY表现为轻度高血糖，除孕期外通常无需治疗。相比之下，某些基因的突变会导致β细胞进行性衰竭，并发症风险与2型糖尿病相似。新生儿糖尿病（NDM）是单基因糖尿病的一种罕见形式，通常在出生后的头六个月内出现。一半的病例为终身性，而其他病例会经历短暂缓解。永久性NDM最常见的原因是编码三磷酸腺苷敏感性钾通道（或）的基因发生激活突变，确诊后可改用磺脲类药物治疗。因此在许多情况下，单基因糖尿病为精准治疗提供了机会。随着下一代测序（NGS）技术的出现，这一领域的范围得到了拓宽，取代了像桑格测序这样的旧方法。NGS可用于靶向基因panel、全外显子组测序（WES）或全基因组测序。靶向基因panel能高效提供特定信息，而WES提供全面数据，但存在生物信息学挑战。检测的激增也导致了意义未明变异（VUS）的增加。判断VUS是致病的还是良性的可能具有挑战性。计算模型、功能研究和临床知识有助于确定致病性。基因检测技术的进步为改善诊断和个性化治疗带来了希望，但也引发了对解读和伦理问题的担忧。
