Piccini Barbara, Artuso Rosangela, Lenzi Lorenzo, Guasti Monica, Braccesi Giulia, Barni Federica, Casalini Emilio, Giglio Sabrina, Toni Sonia
Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children's Hospital, Florence, Italy.
Medical Genetics Unit, Meyer University Children's Hospital, Florence, Italy.
Eur J Med Genet. 2016 Nov;59(11):590-595. doi: 10.1016/j.ejmg.2016.09.016. Epub 2016 Sep 19.
Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.
青年发病的成年型糖尿病（MODY）的正确诊断基于基因检测，而这需要临床医生进行恰当的受试者选择。胰岛素（INS）基因突变在MODY患者中很少发生。本研究旨在确定疑似MODY患者的遗传背景和临床表型。对34例GCK、HNF1α、HNF4α、HNF1β和PDX1基因无突变的疑似MODY患者进行了二代测序（NGS）筛查。在同一家族的4名成员中鉴定出杂合INS突变。首次进行的基因检测在MODY3/HNF1α基因中发现了两个杂合沉默核苷酸替换。尝试停用胰岛素治疗、给予瑞格列奈和磺脲类药物，但未成功。通过对一组102个基因进行NGS重新测序DNA。选择了与胰腺β细胞途径相关的基因、2型糖尿病候选基因以及小鼠糖尿病致病基因。在受影响的家庭成员中发现了人胰岛素原INS基因的一个新的杂合变异（c.125T>C）。新的INS突变拓宽了可能的INS表型谱。不仅在新生儿糖尿病中，而且在MODYx患者以及部分1型糖尿病自身抗体阴性患者中，都有必要筛查INS突变。对于没有特定表型的复杂疾病患者，应通过NGS进行研究，因为桑格测序在检测罕见变异方面效率低下且耗时。
