Minicocci Ilenia, Pozzessere Simone, Prisco Cristina, Montali Anna, di Costanzo Alessia, Martino Eliana, Martino Francesco, Arca Marcello
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
J Pediatr. 2017 Apr;183:100-107.e3. doi: 10.1016/j.jpeds.2016.12.075. Epub 2017 Feb 1.
To evaluate the effectiveness of criteria based on child-parent assessment in predicting familial hypercholesterolemia (FH)-causative mutations in unselected children with hypercholesterolemia.
LDLR, APOB, and PCSK9 genes were sequenced in 78 children and adolescents (mean age 8.4 ± 3.7 years) with clinically diagnosed FH. The presence of polygenic hypercholesterolemia was further evaluated by genotyping 6 low-density lipoprotein cholesterol (LDL-C)-raising single-nucleotide polymorphisms.
Thirty-nine children (50.0%) were found to carry LDLR mutant alleles but none with APOB or PCSK9 mutant alleles. Overall, 27 different LDLR mutations were identified, and 2 were novel. Children carrying mutations showed higher LDL-C (215.2 ± 52.7 mg/dL vs 181.0 ± 44.6 mg/dL, P <.001) and apolipoprotein B levels (131.6 ± 38.3 mg/dL vs 100.3 ± 30.0 mg/dL, P <.004), compared with noncarriers. A LDL-C of ~190 mg/dL was the optimal value to discriminate children with and without LDLR mutations. When different diagnostic criteria were compared, those proposed by the European Atherosclerosis Society showed a reasonable balance between sensitivity and specificity in the identification of LDLR mutations. In children without mutation, the FH phenotype was not caused by the aggregation of LDL-C raising single-nucleotide polymorphisms.
In unselected children with hypercholesterolemia, LDL-C levels >190 mg/dL and a positive family history of hypercholesterolemia appeared to be the most reliable criteria for detecting FH. As 50% of children with suspected FH did not carry FH-causing mutations, genetic testing should be considered.
评估基于儿童-家长评估的标准在预测未选择的高胆固醇血症儿童中家族性高胆固醇血症（FH）致病突变方面的有效性。
对78名临床诊断为FH的儿童和青少年（平均年龄8.4±3.7岁）的低密度脂蛋白受体（LDLR）、载脂蛋白B（APOB）和前蛋白转化酶枯草溶菌素9（PCSK9）基因进行测序。通过对6个升高低密度脂蛋白胆固醇（LDL-C）的单核苷酸多态性进行基因分型，进一步评估多基因高胆固醇血症的存在情况。
发现39名儿童（50.0%）携带LDLR突变等位基因，但未发现携带APOB或PCSK9突变等位基因的儿童。总体而言，共鉴定出27种不同的LDLR突变，其中2种为新突变。与未携带突变的儿童相比，携带突变的儿童LDL-C水平更高（215.2±52.7mg/dL对181.0±44.6mg/dL，P<0.001），载脂蛋白B水平也更高（131.6±38.3mg/dL对100.3±30.0mg/dL，P<0.004）。约190mg/dL的LDL-C是区分携带和未携带LDLR突变儿童的最佳值。当比较不同的诊断标准时，欧洲动脉粥样硬化学会提出的标准在识别LDLR突变方面显示出敏感性和特异性之间的合理平衡。在未发生突变的儿童中，FH表型不是由升高LDL-C的单核苷酸多态性聚集引起的。
在未选择的高胆固醇血症儿童中，LDL-C水平>190mg/dL和高胆固醇血症的阳性家族史似乎是检测FH最可靠的标准。由于50%疑似FH的儿童未携带FH致病突变，应考虑进行基因检测。
