Limitations of exome sequencing in detecting rare and undiagnosed diseases.
Limitations of exome sequencing in detecting rare and undiagnosed diseases.
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DOI：
10.1002/ajmg.a.61558
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发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Undiagnosed Diseases Network
中科院分区：
文献类型：
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作者：
Burdick KJ;Cogan JD;Rives LC;Robertson AK;Koziura ME;Brokamp E;Duncan L;Hannig V;Pfotenhauer J;Vanzo R;Paul MS;Bican A;Morgan T;Duis J;Newman JH;Hamid R;Phillips JA 3rd;Undiagnosed Diseases Network
虽然外显子组测序（ES）通常是临床遗传学的最后诊断步骤，但它可能会错过诊断。为了澄清ES的局限性，我们在未诊断疾病网络（UDN）参与者中调查了超出ES的基因检测的诊出率。我们回顾了其他基因检测的产量，包括基因组测序（GS）、拷贝数变异（CNV）、非编码变异（NCV）、重复扩增（RE）或甲基化检测在非诊断性ES结果的UDN病例中。总体而言，36/54（67%）的诊断基于临床表现和ES发现的编码变异，3/54（6%）的诊断仅基于临床表现。其余15/54（28%）需要ES以外的测试。其中，7/15（47%）患有NCV， 6/15（40%）患有CNV， 2/15（13%）患有RE或DNA甲基化障碍。因此，18/54（33%）的诊断不能完全通过ES解决。需要几种方法来检测和/或确认被ES遗漏的变异的功能影响，在某些情况下被GS遗漏。这些结果表明，在非诊断的初步步骤之后，应该考虑检测难以捉摸的变异。需要进一步的研究来确定除了ES之外的测试的成本效益，这些测试提供了诊断和对可能的治疗的见解。
While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.
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DOI：
10.1038/gim.2017.119
发表时间：
2018-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Lionel AC;Costain G;Monfared N;Walker S;Reuter MS;Hosseini SM;Thiruvahindrapuram B;Merico D;Jobling R;Nalpathamkalam T;Pellecchia G;Sung WWL;Wang Z;Bikangaga P;Boelman C;Carter MT;Cordeiro D;Cytrynbaum C;Dell SD;Dhir P;Dowling JJ;Heon E;Hewson S;Hiraki L;Inbar-Feigenberg M;Klatt R;Kronick J;Laxer RM;Licht C;MacDonald H;Mercimek-Andrews S;Mendoza-Londono R;Piscione T;Schneider R;Schulze A;Silverman E;Siriwardena K;Snead OC;Sondheimer N;Sutherland J;Vincent A;Wasserman JD;Weksberg R;Shuman C;Carew C;Szego MJ;Hayeems RZ;Basran R;Stavropoulos DJ;Ray PN;Bowdin S;Meyn MS;Cohn RD;Scherer SW;Marshall CR
通讯作者：
Marshall CR
影响因子：
2.1
作者：
Shaikh TH
通讯作者：
Shaikh TH
影响因子：
158.5
作者：
Splinter, K.;Adams, D. R.;Ashley, E. A.
通讯作者：
Ashley, E. A.
影响因子：
1.9
作者：
Nolan, Danielle;Carlson, Martha
通讯作者：
Carlson, Martha
影响因子：
5.3
作者：
Meienberg J;Bruggmann R;Oexle K;Matyas G
通讯作者：
Matyas G