Exome sequencing in suspected monogenic dyslipidemias.
Exome sequencing in suspected monogenic dyslipidemias.
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DOI：
10.1161/circgenetics.114.000776
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
Kathiresan S
中科院分区：
文献类型：
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作者：
Stitziel NO;Peloso GM;Abifadel M;Cefalu AB;Fouchier S;Motazacker MM;Tada H;Larach DB;Awan Z;Haller JF;Pullinger CR;Varret M;Rabès JP;Noto D;Tarugi P;Kawashiri MA;Nohara A;Yamagishi M;Risman M;Deo R;Ruel I;Shendure J;Nickerson DA;Wilson JG;Rich SS;Gupta N;Farlow DN;Neale BM;Daly MJ;Kane JP;Freeman MW;Genest J;Rader DJ;Mabuchi H;Kastelein JJ;Hovingh GK;Averna MR;Gabriel S;Boileau C;Kathiresan S
外显子组测序是孟德尔疾病基因定位的一种很有前途的工具。我们利用这项技术试图确定单基因血脂异常的新基因。我们对来自41个疑似孟德尔遗传极端水平的低密度脂蛋白胆固醇(LDL)胆固醇(在候选基因测序排除了高密度脂蛋白胆固醇家族的已知遗传原因后)或高密度脂蛋白胆固醇(HDL)家族的213名家庭成员进行了外显子组测序。我们使用标准的分析方法来确定候选变异，并为每个个体分配一个多基因评分，以说明他们对已知影响血脂水平的常见遗传变异的负担。在9个家系中，我们发现了已知脂类基因(ABCA1、APOB、APOE、LDLR、LIPA和PCSK9)中可能的致病变异；然而，尽管进行了随访分析，我们仍无法在其余32个家系中确定明显的遗传病因。我们发现了三个限制新基因发现的因素：(1)外显子组不完善的测序覆盖范围隐藏了潜在的因果变异；(2)家庭内大量共享的稀有等位基因混淆了因果变异的识别；(3)来自15%的家庭的个体携带了显著的常见脂类相关等位基因，这表明复杂的遗传可能伪装成单基因疾病。我们在41个家系中的9个家系中确定了疾病的遗传基础；然而，这些家庭中没有一个代表新的基因发现。我们的结果强调了外显子组测序作为可疑的单基因血脂异常的一种发现技术的前景和局限性。考虑到已确定的混杂因素可能会为未来外显子组测序研究的设计提供参考。
Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.