Montreal Children's Hospital and the Endocrine Genetics Laboratory, Child Health and Human Development Program, the Research Institute of the McGill University Health Centre, Montreal, Canada.
Clinical Research Center, Maoming People's Hospital, Guangdong, China.
J Clin Endocrinol Metab. 2021 May 13;106(6):1804-1810. doi: 10.1210/clinem/dgab056.
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.
约 1%的临床诊断为 1 型糖尿病的患者患有非自身免疫性单基因糖尿病。这种区分具有重要的治疗意义，但鉴于检测的患病率低且成本高，选择要检测的患者很重要。我们检验了低 1 型糖尿病遗传风险是否可以对此选择产生重大影响的假设。
作为原理验证，我们通过外显子组测序检查了 2 个或更多孩子的家庭，这些家庭是由 1 型糖尿病遗传学联合会（T1DGC）招募的，并选择了 2 种自身抗体阴性和不存在风险人类白细胞抗原单倍型的家庭。
我们检查了符合标准的 46 个家庭。在有患病父母的 17 个家庭中，有 7 个（41.2%）存在可治疗的单基因变异。在没有患病父母的 29 个家庭中，有 14 个（48.3%）存在此类变异，其中包括 5 个具有 WFS1 的隐性致病性变异，但没有报道其他 Wolfram 综合征的特征。我们的方法通过仅对 11.1%的自身抗体阴性者进行测序，诊断出整个 T1DGC 队列中估计的单基因家族的 55.8%，这是合理的。
我们的发现证明，即使没有患病父母，使用自身免疫标志物进行大规模前瞻性筛选研究也是合理的。我们还证实，非综合征性 WFS1 变异在被误诊为 1 型糖尿病的单基因糖尿病病例中很常见。
