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The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
Frontiers in Genetics ( IF 3.7 ) Pub Date : 2020-12-01 , DOI: 10.3389/fgene.2020.572045
Amina Kamar , Athar Khalil , Georges Nemer

Genetically inherited defects in lipoprotein metabolism affect more than 10 million individuals around the globe with preponderance in some parts where consanguinity played a major role in establishing founder mutations. Mutations in four genes have been so far linked to the dominant and recessive form of the disease. Those players encode major proteins implicated in cholesterol regulation, namely, the low-density lipoprotein receptor (LDLR) and its associate protein 1 (LDLRAP1), the proprotein convertase substilin/kexin type 9 (PCSK9), and the apolipoprotein B (APOB). Single mutations or compound mutations in one of these genes are enough to account for a spectrum of mild to severe phenotypes. However, recently several reports have identified digenic mutations in familial cases that do not necessarily reflect a much severe phenotype. Yet, data in the literature supporting this notion are still lacking. Herein, we review all the reported cases of digenic mutations focusing on the biological impact of gene dosage and the potential protective effects of single-nucleotide polymorphisms linked to hypolipidemia. We also highlight the difficulty of establishing phenotype–genotype correlations in digenic familial hypercholesterolemia cases due to the complexity and heterogeneity of the phenotypes and the still faulty in silico pathogenicity scoring system. We finally emphasize the importance of having a whole exome/genome sequencing approach for all familial cases of familial hyperlipidemia to better understand the genetic and clinical course of the disease.



中文翻译:

家族性高胆固醇血症的双基因因果关系:修订疾病的基因型-表型相关性。

脂蛋白代谢的遗传遗传缺陷在全球影响着超过1000万个体,其中血缘关系在建立创始人突变中起着重要作用。到目前为止,四个基因的突变与该疾病的显性和隐性形式有关。这些参与者编码涉及胆固醇调节的主要蛋白,即低密度脂蛋白受体(LDLR)及其相关蛋白1(LDLRAP1),前蛋白转化酶Substilin / kexin 9型(PCSK9)和载脂蛋白B(APOB)。这些基因之一中的单突变或复合突变足以说明轻度至重度表型的光谱。但是,最近有几篇报道鉴定出家族性病例中的双基因突变并不一定反映出非常严重的表型。然而,文献中仍然缺乏支持该概念的数据。本文中,我们回顾了所有报道的双基因突变病例,重点关注基因剂量的生物学影响以及与低血脂症相关的单核苷酸多态性的潜在保护作用。我们还强调了由于基因型的复杂性和异质性以及仍然存在缺陷,在双基因家族性高胆固醇血症病例中难以建立表型与基因型的相关性在计算机上致病性评分系统。我们最后强调,对于所有家族性高脂血症的家族病例,采用完整的外显子/基因组测序方法以更好地了解该疾病的遗传和临床过程的重要性。

更新日期:2021-01-16
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