PDF(Pubmed)
Abstract：
About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection.
As proof of principle, we examined by exome sequencing families with 2 or more children, recruited by the Type 1 Diabetes Genetics Consortium (T1DGC) and selected for negativity for 2 autoantibodies and absence of risk human leukocyte antigen haplotypes.
We examined 46 families that met the criteria. Of the 17 with an affected parent, 7 (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including 5 with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones.
Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that nonsyndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.
As proof of principle, we examined by exome sequencing families with 2 or more children, recruited by the Type 1 Diabetes Genetics Consortium (T1DGC) and selected for negativity for 2 autoantibodies and absence of risk human leukocyte antigen haplotypes.
We examined 46 families that met the criteria. Of the 17 with an affected parent, 7 (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including 5 with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones.
Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that nonsyndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.
摘要：
临床诊断为1型糖尿病的患者中约有1％患有非自身免疫性单基因糖尿病。这种区别具有重要的治疗意义，但是，鉴于检测的低患病率和高成本，选择患者进行测试很重要。我们检验了以下假设：1型糖尿病的低遗传风险可以在很大程度上有助于这种选择。
作为原理的证明,我们通过外显子组测序研究了有两个或更多孩子的家庭，由1型糖尿病遗传学联盟（T1DGC）招募，并选择2种自身抗体阴性且不存在风险人类白细胞抗原单倍型。
我们检查了46个符合标准的家庭。在有受影响父母的17人中，7(41.2%)具有可操作的单基因变异。在29个没有受影响父母的家庭中，14人(48.3%)有这样的变异，包括5例WFS1隐性致病变异，但没有其他Wolfram综合征特征的报道。我们的方法诊断了整个T1DGC队列中估计数量的单基因家族的55.8％，通过仅对自身抗体阴性的11.1%进行测序。
我们的发现证明了使用自身免疫标志物进行大规模前瞻性筛查研究的合理性。即使没有受影响的父母。我们还证实，非综合征性WFS1变异在误诊为1型糖尿病的单基因糖尿病病例中很常见。
作为原理的证明,我们通过外显子组测序研究了有两个或更多孩子的家庭，由1型糖尿病遗传学联盟（T1DGC）招募，并选择2种自身抗体阴性且不存在风险人类白细胞抗原单倍型。
我们检查了46个符合标准的家庭。在有受影响父母的17人中，7(41.2%)具有可操作的单基因变异。在29个没有受影响父母的家庭中，14人(48.3%)有这样的变异，包括5例WFS1隐性致病变异，但没有其他Wolfram综合征特征的报道。我们的方法诊断了整个T1DGC队列中估计数量的单基因家族的55.8％，通过仅对自身抗体阴性的11.1%进行测序。
我们的发现证明了使用自身免疫标志物进行大规模前瞻性筛查研究的合理性。即使没有受影响的父母。我们还证实，非综合征性WFS1变异在误诊为1型糖尿病的单基因糖尿病病例中很常见。
