背景:非典型非自身免疫性糖尿病的诊断,如年轻人的成熟型糖尿病(MODY)提出了几个挑战,鉴于该疾病广泛的临床和遗传异质性。在本报告中,我们描述了与破坏性HNF1β突变相关的非典型非自身免疫性糖尿病病例。这是通过一些非特征性的临床特征来区分的,包括早发性肥胖,没有肾囊肿和糖尿病肾病。HNF1β-MODY(MODY5)是一种罕见的单基因糖尿病,通常因一系列先天性尿路形态异常而复杂化。包括肾囊肿.本报告扩展了在HNF1β突变的背景下描述的临床表型,并且是相关的,因为仅报道了MODY5设置中的糖尿病肾病的孤立病例。
方法:一名患有非自身免疫性糖尿病的肥胖马耳他女性,微量白蛋白尿,肾小球滤过过度,我们通过全外显子组测序研究了脂肪肝和无肾囊肿,以研究与先证者表型相关的潜在基因。鉴定出HNF1β外显子8高度保守位点的罕见错义突变(c.1580G>A,NM_000458.3,p.Arg527Gln),多个计算机内预测与致病性一致。这种突变以前没有被表征。此外,与早发性肥胖相关的几种常见易感性变异,在先证者中发现了多基因2型糖尿病和肾病,可能对表型产生额外影响,其严重程度或临床过程。
结论:本报告强调了与HNF1β错义突变相关的非典型糖尿病先证者的一些非典型特征。它还强化了糖尿病的单基因原因可能是患有非典型糖尿病的肥胖个体的疾病负担的重要因素的概念。
BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging
HNF1β mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy.
HNF1β-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of
HNF1β mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported.
METHODS: An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband\'s phenotype. A rare missense mutation at a highly conserved site in exon 8 of
HNF1β was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course.
CONCLUSIONS: This report highlights several atypical features in a proband with atypical diabetes associated with an
HNF1β missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.