Genotype and Phenotype Correlations in 417 Children With Congenital Hyperinsulinism
Genotype and Phenotype Correlations in 417 Children With Congenital Hyperinsulinism
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DOI：
10.1210/jc.2012-2169
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发表时间：
2013-02-01
影响因子：
5.8
通讯作者：
Ganguly, A.
中科院分区：
文献类型：
--
作者：
Snider, K. E.;Becker, S.;Ganguly, A.
目的：对417例先天性高胰岛素血症(HI)患儿进行ATP敏感性钾通道基因(ABCC8和KCNJ11)、GLUD1和GCK的突变分析，并补充筛选更罕见的基因HADH、UCP2、HNF4a、HNF1a和SLC16A1。结果：91%(272/298)的二氮卓不反应前带(CC8、KCNJ11和GCK)和47%(56/118)的二氮卓前体带(AB8、KCNJ11、GLUD1、HADH、HNF1a和SLC16A1)发生突变。UCP2、HNF4a和HNF1a)。在二氮卓无反应的弥漫性先证者中，89%(109/122)携带KATP突变；2%(2/122)携带GCK突变。在突变阳性的二氮卓反应先证者中，42%是GLUD1，41%是显性KATP突变，16%是罕见基因(HADH、UCP2、HNF4a和HNF1a)。在183个独特的KATP突变中，70%在鉴定时是新的。局灶性HI在282例二氮卓无反应先证者中占53%(149例)；97%(149例中的145例)可检测到单等位基因隐性KATP突变(在所有被测试的病例中排除了母系传播)。单等位基因隐性KATP突变预测局灶性HI的敏感度为97%，特异度为90%。结论：在GLUD1、GCK和KATP隐性突变的儿童中，基因型与表型的相关性最成功。新的错义KATP突变的高频率使相关性变得复杂，因为这种缺陷可能是隐性的，也可能是显性的，如果是显性的，则对二氮卓有反应或无反应。基于基因型的准确和及时的表型预测对于限制先天性HI婴儿和儿童暴露于持续性低血糖至关重要。(J临床内分泌Metab 98：E355-E363,2013)
Context: Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes.Objective: Our objective was to correlate genotype with phenotype in 417 children with HI.Methods: Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1.Results: Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxide-unresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity.Conclusions: Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI. (J Clin Endocrinol Metab 98: E355-E363, 2013)