Intricacies of aetiology in intrafamilial degenerative disease.
Intricacies of aetiology in intrafamilial degenerative disease.
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家族内退行性疾病病因学的复杂性。
DOI：
10.1093/braincomms/fcaa120
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发表时间：
2020
影响因子：
4.8
通讯作者：
Siddique T
中科院分区：
文献类型：
--
作者：
Lowry JL;Ryan ÉB;Esengul YT;Siddique N;Siddique T
迟发性退行性疾病的遗传基础通常是通过筛查受影响但并非未受影响的个体中具有疾病特征的遗传变异的家族分离来确定的。然而，家族内病因异质性的例子，即致病基因的致病变异在所有受影响的家庭成员中并不共享，继续出现并混淆了基因发现和遗传咨询的努力。不一致的家族内病例缺乏其他受影响家庭成员共有的突变，被描述为疾病表型。这种描述往往导致过度简化地接受表型病例中疾病的环境原因，而家族内遗传异质性、共同的新生突变或这些家庭中的表观遗传畸变的作用往往被忽视。与此相关的是，现在很明显，相同的疾病相关变异可以出现在表现出临床不同表型的个体中，从而在遗传上将看似不相关的综合征结合起来，形成疾病谱系。在此，我们讨论了确定复杂退行性疾病病因的复杂性，并提出了疾病传播的替代机制，这些机制可能解释了疾病明显缺失的遗传性。本综述解决了将明显不一致的疾病病因分类为表型的缺陷，提供了遗传性疾病传播的替代解释，并讨论了多效性基因在退行性疾病中的复杂作用。
The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogenic variants in a culprit gene are not shared among all affected family members, continue to emerge and confound gene-discovery and genetic counselling efforts. Discordant intrafamilial cases lacking a mutation shared by other affected family members are described as disease phenocopies. This description often results in an over-simplified acceptance of an environmental cause of disease in the phenocopy cases, while the role of intrafamilial genetic heterogeneity, shared de novo mutations or epigenetic aberrations in such families is often ignored. On a related note, it is now evident that the same disease-associated variant can be present in individuals exhibiting clinically distinct phenotypes, thereby genetically uniting seemingly unrelated syndromes to form a spectrum of disease. Herein, we discuss the intricacies of determining complex degenerative disease aetiology and suggest alternative mechanisms of disease transmission that may account for the apparent missing heritability of disease. This review addresses the pitfalls of classifying cases of apparently discordant disease aetiology as phenocopies, offers alternative explanations for hereditary disease transmission and discusses the complex roles of pleiotropic genes in degenerative disease.
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影响因子：
12.3
作者：
Acuna-Hidalgo R;Veltman JA;Hoischen A
通讯作者：
Hoischen A
DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
25
作者：
Chesi, Alessandra;Staahl, Brett T.;Jovicic, Ana;Couthouis, Julien;Fasolino, Maria;Raphael, Alya R.;Yamazaki, Tomohiro;Elias, Laura;Polak, Meraida;Kelly, Crystal;Williams, Kelly L.;Fifita, Jennifer A.;Maragakis, Nicholas J.;Nicholson, Garth A.;King, Oliver D.;Reed, Robin;Crabtree, Gerald R.;Blair, Ian P.;Glass, Jonathan D.;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
3.9
作者：
DeJesus-Hernandez, Mariely;Kocerha, Jannet;Finch, NiCole;Crook, Richard;Baker, Matt;Desaro, Pamela;Johnston, Amelia;Rutherford, Nicola;Wojtas, Aleksandra;Kennelly, Kathleen;Wszolek, Zbigniew K.;Graff-Radford, Neill;Boylan, Kevin;Rademakers, Rosa
通讯作者：
Rademakers, Rosa
影响因子：
3.5
作者：
Al-Chalabi, A;Andersen, PM;Powell, JF
通讯作者：
Powell, JF