Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype
Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype
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DOI：
10.1016/j.atherosclerosissup.2019.01.006
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发表时间：
2019-03-01
影响因子：
--
通讯作者：
Gaspar, A.
中科院分区：
文献类型：
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作者：
Gaspar, I. M.;Gaspar, A.
家族性高胆固醇血症是以低密度脂蛋白受体（LDLR）缺陷为特征的孟德尔显性疾病，其导致从血浆中去除LDL的缺陷，这促进了胆固醇在皮肤中的沉积（黄瘤），肌腱（黄色瘤）和动脉（动脉粥样硬化）。使用荷兰脂质临床网络标准诊断严重临床表型FH，包括过早ASCVD、肌腱黄色瘤病史，在葡萄牙FH患者中，亲属中有高胆固醇血症和过早ASCVD的家族史是罕见的。临床诊断或基因突变的FH个体表型存在变异性（携带者和患者）可能是由于上世纪的环境因素，地中海饮食，或不含脂肪食物的饮食，反式脂肪食物，不吸烟，不久坐不动的生活会干扰我们的新陈代谢，或者是多基因，表观遗传，后天缺陷的后果，修饰基因和β-珠蛋白无症状携带者。我们在遗传学中有几个概念/机制与遗传性疾病是横向的，在FH中很常见，例如体细胞嵌合体，老年嵌合体，突变的可变表达和可变突变率。血液基因检测结果阴性并不能排除FH，因为致病性LDLR突变只能在肝脏中表达，（体细胞组织中的突变）或偶尔通过生殖细胞系上的突变-生殖细胞嵌合体从伴侣垂直传播给未来的孩子。与北欧国家不同，大多数FH携带者和患者的表型不那么严重，例如，有儿童和年轻成人携带者的LDL-R突变具有正常的TC和LDL-C，老年妇女具有较温和的表型，没有ASCVD事件，肌腱黄色瘤见于
Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis).Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers.We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations.A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism.Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in