Genetic testing for familial hypercholesterolemia-past, present, and future.
Genetic testing for familial hypercholesterolemia-past, present, and future.
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DOI：
10.1016/j.jlr.2021.100139
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发表时间：
2021
影响因子：
6.5
通讯作者：
Humphries SE
中科院分区：
文献类型：
--
作者：
Futema M;Taylor-Beadling A;Williams M;Humphries SE
在20世纪80年代早期，Mike Brown和Joe Goldstein的诺贝尔奖获得者细胞和分子工作导致LDL受体基因被鉴定为第一个突变导致家族性高胆固醇血症（FH）表型的基因。我们现在知道，常染色体显性单基因FH可由另外三种基因（APOB/PCSK 9/APOE）的致病性变体引起，并且血浆LDL-C浓度和早发冠心病的风险根据特定基因座和相关分子原因而不同。现在可以使用下一代测序技术对所有四个基因的所有外显子进行测序，在一次测序运行中处理96个患者样本，提高检测结果的速度，降低成本。这导致不仅鉴定出许多新的FH引起的变体，而且鉴定出一些意义未知的变体，这些变体需要进一步的证据来分类为致病性或良性。在索引情况下，FH引起的变异的识别可以用作其他家庭成员的明确和快速的测试。在20-40%具有FH表型的患者中可以发现FH引起的变体，并且我们现在认识到，在大多数没有单基因病因的患者中，其表型的多基因病因非常可能。与单基因病因的患者相比，这些患者未来患冠心病的风险显著降低。这些分子遗传学诊断方法在FH表征中的使用是精确或个性化医学实用性的主要例子。
In the early 1980s, the Nobel Prize winning cellular and molecular work of Mike Brown and Joe Goldstein led to the identification of the LDL receptor gene as the first gene where mutations cause the familial hypercholesterolemia (FH) phenotype. We now know that autosomal dominant monogenic FH can be caused by pathogenic variants of three additional genes (APOB/PCSK9/APOE) and that the plasma LDL-C concentration and risk of premature coronary heart disease differs according to the specific locus and associated molecular cause. It is now possible to use next-generation sequencing to sequence all exons of all four genes, processing 96 patient samples in one sequencing run, increasing the speed of test results, and reducing costs. This has resulted in the identification of not only many novel FH-causing variants but also some variants of unknown significance, which require further evidence to classify as pathogenic or benign. The identification of the FH-causing variant in an index case can be used as an unambiguous and rapid test for other family members. An FH-causing variant can be found in 20–40% of patients with the FH phenotype, and we now appreciate that in the majority of patients without a monogenic cause, a polygenic etiology for their phenotype is highly likely. Compared with those with a monogenic cause, these patients have significantly lower risk of future coronary heart disease. The use of these molecular genetic diagnostic methods in the characterization of FH is a prime example of the utility of precision or personalized medicine.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
5.3
作者：
Futema M;Whittall RA;Kiley A;Steel LK;Cooper JA;Badmus E;Leigh SE;Karpe F;Neil HA;Simon Broome Register Group;Humphries SE
通讯作者：
Humphries SE
DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Bogsrud, Martin P.;Graesdal, Asgeir;Holven, Kirsten B.
通讯作者：
Holven, Kirsten B.
影响因子：
3.7
作者：
Duskova, Lucie;Nohelova, Lucie;Fajkusova, Lenka
通讯作者：
Fajkusova, Lenka