Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry
Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry
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DOI：
10.1007/s00125-016-4167-1
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发表时间：
2017-04-01
期刊：
影响因子：
8.2
通讯作者：
Njolstad, Pal R.
中科院分区：
文献类型：
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作者：
Johansson, Bente B.;Irgens, Henrik U.;Njolstad, Pal R.
AIMS/假说MODY可能被误诊为儿童1型糖尿病。方法采用下一代测序技术，对469名GAD和IA-2自身抗体均阴性的儿童(12.1%)和挪威儿童糖尿病登记处的469名抗体匹配的对照儿童(3882名)进行HNF1A、HNF4a、HNF1B、GCK和INS基因筛查。根据致病性的临床诊断标准对变异进行分类，范围从1类(中性)到5类(致病)。结果我们在病例和对照中发现了58个罕见的外显子和剪接变异。在抗体阴性患者中，6.5%的患者有3-5类基因变异(对照组为2.4%；p=0.002)。对于更严格的分类(4级和5级)，相应的数字为4.1%(对照组为0.2%；p=1.6x10-5)。HNF1a显示了3-5类变异的最强富集性，抗体阴性患者中有3.9%(对照组为0.4%；p=0.0002)。3类抗体阴性变异体携带者的表型与4类和5类变异体携带者相似。结论/解释这是全国人群登记中首次对所有抗体阴性儿童进行MODY研究筛查。我们的结果表明，抗体阴性的儿童糖尿病患者的MODY患病率可能达到6.5%。其中三分之一的MODY病例没有得到临床医生的认可。由于准确的诊断对治疗和遗传咨询很重要，在常规诊断中应考虑对所有抗体阴性儿童进行分子筛查。
Aims/hypothesis MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes.Methods Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic).Results We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p= 1.6x10-5). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5.Conclusions/interpretation This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.