Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center's experience

被引：142

作者：

Valencia, C. Alexander ^{[1
,2
]}

Husami, Ammar ^{[1
,2
]}

Holle, Jennifer ^{[1
,2
]}

Johnson, Judith A. ^{[1
,2
]}

Qian, Yaping ^{[3
]}

Mathur, Abhinav ^{[1
,2
]}

Wei, Chao ^{[1
,2
]}

Indugula, Subba Rao ^{[1
,2
]}

Zou, Fanggeng ^{[1
,2
]}

Meng, Haiying ^{[1
,2
]}

Wang, Lijun ^{[1
,2
]}

Li, Xia ^{[1
,2
]}

Fisher, Rachel ^{[1
,2
]}

Tan, Tony ^{[1
,2
]}

Begtrup, Amber Hogart ^{[1
,2
]}

Collins, Kathleen ^{[1
,2
]}

Wusik, Katie A. ^{[1
,2
]}

Neilson, Derek ^{[1
,2
]}

Burrow, Thomas ^{[1
,2
]}

Schorry, Elizabeth ^{[1
,2
]}

Hopkin, Robert ^{[1
,2
]}

Keddache, Mehdi ^{[1
,2
]}

Harley, John Barker ^{[2
,4
,5
]}

Kaufman, Kenneth M. ^{[2
,4
,5
]}

Zhang, Kejian ^{[1
,2
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, 3333 Burnet Ave,MLC7016, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA

[3] Myriad Genet Labs Inc, Salt Lake City, UT USA

[4] Cincinnati Childrens Hosp Med Ctr, CAGE, Cincinnati, OH 45229 USA

[5] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA

来源：

FRONTIERS IN PEDIATRICS | 2015年 / 3卷

关键词：

whole exome sequencing; next generation sequencing; diagnosis; children; clinical utility; pediatrics;

D O I：

10.3389/fped.2015.00067

中图分类号：

R72 [儿科学];

学科分类号：

100202 ;

摘要：

Background: There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES. Objective: We demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered. Moreover, we examined the potential cost-effectiveness of WES by examining the cost burden of diagnostic workups. Methods: To determine the clinical utility of our hospital's clinical WES, we performed a retrospective review of the first 40 cases. We utilized dual bioinformatics analyses pipelines based on commercially available software and in-house tools. Results: Of the first 40 clinical cases, we identified genetic defects in 12 (30%) patients, of which 47% of the mutations were previously unreported in the literature. Among the 12 patients with positive findings, seven have autosomal dominant disease and five have autosomal recessive disease. Ninety percent of the cohort opted to receive secondary findings and of those, secondary medical actionable results were returned in three cases. Among these positive cases, there are a number of novel mutations that are being reported here. The diagnostic workup included a significant number of genetic tests with microarray and single-gene sequencing being the most popular tests. Significantly, genetic diagnosis from WES led to altered patient medical management in positive cases. Conclusion: We demonstrate the clinical utility of WES by establishing the clinical diagnostic rate and its impact on medical management in a large pediatric center. The cost-effectiveness of WES was demonstrated by ending the diagnostic odyssey in positive cases. Also, in some cases it may be most cost-effective to directly perform WES. WES provides a unique glimpse into the complexity of genetic disorders.

引用

页数：15

共 55 条

[1] De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome [J].

Bainbridge, Matthew N. ;

Hu, Hao ;

Muzny, Donna M. ;

Musante, Luciana ;

Lupski, James R. ;

Graham, Brett H. ;

Chen, Wei ;

Gripp, Karen W. ;

Jenny, Kim ;

Wienker, Thomas F. ;

Yang, Yaping ;

Sutton, V. Reid ;

Gibbs, Richard A. ;

Ropers, H. Hilger .

GENOME MEDICINE, 2013, 5

[2] Whole-Genome Sequencing for Optimized Patient Management [J].

Bainbridge, Matthew N. ;

Wiszniewski, Wojciech ;

Murdock, David R. ;

Friedman, Jennifer ;

Gonzaga-Jauregui, Claudia ;

Newsham, Irene ;

Reid, Jeffrey G. ;

Fink, John K. ;

Morgan, Margaret B. ;

Gingras, Marie-Claude ;

Muzny, Donna M. ;

Hoang, Linh D. ;

Yousaf, Shahed ;

Lupski, James R. ;

Gibbs, Richard A. .

SCIENCE TRANSLATIONAL MEDICINE, 2011, 3 (87)

[3] Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency [J].

Chen, Karin ;

Coonrod, Emily M. ;

Kumanovics, Attila ;

Franks, Zechariah F. ;

Durtschi, Jacob D. ;

Margraf, Rebecca L. ;

Wu, Wilfred ;

Heikal, Nahla M. ;

Augustine, Nancy H. ;

Ridge, Perry G. ;

Hill, Harry R. ;

Jorde, Lynn B. ;

Weyrich, Andrew S. ;

Zimmerman, Guy A. ;

Gundlapalli, Adi V. ;

Bohnsack, John F. ;

Voelkerding, Karl V. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 93 (05) :812-824

[4] Chronic non-paroxysmal neuropathic pain - Novel phenotype of mutation in the sodium channel SCN9A gene [J].

Dabby, Ron ;

Sadeh, Menachem ;

Gilad, Ronit ;

Lampl, Yair ;

Cohen, Sarit ;

Inbar, Shani ;

Leshinsky-Silver, Esther .

JOURNAL OF THE NEUROLOGICAL SCIENCES, 2011, 301 (1-2) :90-92

[5] Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability [J].

de Ligt, Joep ;

Willemsen, Marjolein H. ;

van Bon, Bregje W. M. ;

Kleefstra, Tjitske ;

Yntema, Helger G. ;

Kroes, Thessa ;

Vulto-van Silfhout, Anneke T. ;

Koolen, David A. ;

de Vries, Petra ;

Gilissen, Christian ;

del Rosario, Marisol ;

Hoischen, Alexander ;

Scheffer, Hans ;

de Vries, Bert B. A. ;

Brunner, Han G. ;

Veltman, Joris A. ;

Vissers, Lisenka E. L. M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (20) :1921-1929

[6] An exome sequencing strategy to diagnose lethal autosomal recessive disorders [J].

Ellard, Sian ;

Kivuva, Emma ;

Turnpenny, Peter ;

Stals, Karen ;

Johnson, Matthew ;

Xie, Weijia ;

Caswell, Richard ;

Allen, Hana Lango .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2015, 23 (03) :401-404

[7] Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy [J].

Faber, Catharina G. ;

Hoeijmakers, Janneke G. J. ;

Ahn, Hye-Sook ;

Cheng, Xiaoyang ;

Han, Chongyang ;

Choi, Jin-Sung ;

Estacion, Mark ;

Lauria, Giuseppe ;

Vanhoutte, Els K. ;

Gerrits, Monique M. ;

Dib-Hajj, Sulayman ;

Drenth, Joost P. H. ;

Waxman, Stephen G. ;

Merkies, Ingemar S. J. .

ANNALS OF NEUROLOGY, 2012, 71 (01) :26-39

[8] The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases [J].

Gahl, William A. ;

Markello, Thomas C. ;

Toro, Camilo ;

Fajardo, Karin Fuentes ;

Sincan, Murat ;

Gill, Fred ;

Carlson-Donohoe, Hannah ;

Gropman, Andrea ;

Pierson, Tyler Mark ;

Golas, Gretchen ;

Wolfe, Lynne ;

Groden, Catherine ;

Godfrey, Rena ;

Nehrebecky, Michele ;

Wahl, Colleen ;

Landis, Dennis M. D. ;

Yang, Sandra ;

Madeo, Anne ;

Mullikin, James C. ;

Boerkoel, Cornelius F. ;

Tifft, Cynthia J. ;

Adams, David .

GENETICS IN MEDICINE, 2012, 14 (01) :51-59

[9] Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome [J].

Giunta, C ;

Nuytinck, L ;

Raghunath, M ;

Hausser, I ;

De Paepe, A ;

Steinmann, B .

AMERICAN JOURNAL OF MEDICAL GENETICS, 2002, 109 (04) :284-290

[10] Human Genome Sequencing in Health and Disease [J].

Gonzaga-Jauregui, Claudia ;

Lupski, James R. ;

Gibbs, Richard A. .

ANNUAL REVIEW OF MEDICINE, VOL 63, 2012, 63 :35-61

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