Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

被引：260

作者：

Zhu, Xiaolin ^{[1
]}

Petrovski, Slave ^{[1
,2
,3
]}

Xie, Pingxing ^{[1
]}

Ruzzo, Elizabeth K. ^{[1
]}

Lu, Yi-Fan ^{[1
]}

McSweeney, K. Melodi ^{[1
]}

Ben-Zeev, Bruria ^{[4
,5
]}

Nissenkorn, Andreea ^{[4
,5
]}

Anikster, Yair ^{[4
,5
]}

Oz-Levi, Danit ^{[6
]}

Dhindsa, Ryan S. ^{[1
]}

Hitomi, Yuki ^{[1
]}

Schoch, Kelly ^{[7
]}

Spillmann, Rebecca C. ^{[1
]}

Heimer, Gali ^{[4
,8
]}

Marek-Yagel, Dina ^{[9
]}

Tzadok, Michal ^{[4
,5
]}

Han, Yujun ^{[1
]}

Worley, Gordon ^{[7
]}

Goldstein, Jennifer ^{[7
]}

Jiang, Yong-Hui ^{[7
,10
]}

Lancet, Doron ^{[6
]}

Pras, Elon ^{[4
,11
]}

Shashi, Vandana ^{[7
]}

McHale, Duncan ^{[12
]}

Need, Anna C. ^{[1
,13
]}

Goldstein, David B. ^{[1
]}

机构：

[1] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27708 USA

[2] Univ Melbourne, Austin Hlth, Dept Med, Melbourne, Vic, Australia

[3] Royal Melbourne Hosp, Melbourne, Vic, Australia

[4] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Ramat Gan, Israel

[5] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel

[6] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel

[7] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA

[8] Chaim Sheba Med Ctr, Pinchas Borenstein Talpiot Med Leadership Program, Pediat Neurol Unit, IL-52621 Tel Hashomer, Israel

[9] Edmond & Lily Childrens Hosp, Chaim Sheba Med Ctr, Metab Dis Unit, Ramat Gan, Israel

[10] Duke Univ, Dept Neurobiol, Durham, NC USA

[11] Chaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Ramat Gan, Israel

[12] UCB NewMed, Slough, Berks, England

[13] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Brain Sci, London, England

来源：

GENETICS IN MEDICINE | 2015年 / 17卷 / 10期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

diagnosis; genic intolerance; HNRNPU; rare disease; whole-exome sequencing; DE-NOVO MUTATIONS; FRAMEWORK; PROTEIN; CHILDREN; GENOME;

D O I：

10.1038/gim.2014.191

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene-disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 ( 24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice ( P = 3.4 x 10(-8)). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.

引用

页码：774 / 781

页数：8

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