Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test
Purpose Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides...
Gespeichert in:
| Veröffentlicht in: | Genetics in medicine 2018-04, Vol.20 (4), p.435-443 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 443 |
|---|---|
| container_issue | 4 |
| container_start_page | 435 |
| container_title | Genetics in medicine |
| container_volume | 20 |
| creator | Lionel, Anath C Costain, Gregory Monfared, Nasim Walker, Susan Reuter, Miriam S Hosseini, S Mohsen Thiruvahindrapuram, Bhooma Merico, Daniele Jobling, Rebekah Nalpathamkalam, Thomas Pellecchia, Giovanna Sung, Wilson W L Wang, Zhuozhi Bikangaga, Peter Boelman, Cyrus Carter, Melissa T Cordeiro, Dawn Cytrynbaum, Cheryl Dell, Sharon D Dhir, Priya Dowling, James J Heon, Elise Hewson, Stacy Hiraki, Linda Inbar-Feigenberg, Michal Klatt, Regan Kronick, Jonathan Laxer, Ronald M Licht, Christoph MacDonald, Heather Mercimek-Andrews, Saadet Mendoza-Londono, Roberto Piscione, Tino Schneider, Rayfel Schulze, Andreas Silverman, Earl Siriwardena, Komudi Snead, O Carter Sondheimer, Neal Sutherland, Joanne Vincent, Ajoy Wasserman, Jonathan D Weksberg, Rosanna Shuman, Cheryl Carew, Chris Szego, Michael J Hayeems, Robin Z Basran, Raveen Stavropoulos, Dimitri J Ray, Peter N Bowdin, Sarah Meyn, M Stephen Cohn, Ronald D Scherer, Stephen W Marshall, Christian R |
| description | Purpose
Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.
Methods
We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.
Results
WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%;
P
= 0.01). Genes clinically sequenced in the cohort (
n
= 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes
PIGG
,
RNU4ATAC
,
TRIO
, and
UNC13A
.
Conclusion
WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort. |
| doi_str_mv | 10.1038/gim.2017.119 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5895460</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2023381557</sourcerecordid><originalsourceid>FETCH-LOGICAL-c493t-bbd06660e82c45bcb7fcc55486a5edd8568fc6457922c59182b9343d93b4990f3</originalsourceid><addsrcrecordid>eNptkU9v1DAQxSMEoqVw44wsceFAFv-JHfuCVFUFKlXiAmfLcSZZV0kcbG-rfgs-cmfZUiji5LHeb954_KrqNaMbRoX-MIZ5wylrN4yZJ9Uxk4LWVCj1FGtqdC0UpUfVi5yvKFKC0-fVEddty7hkx9XPi3lN8Rp60gc3LjGX4MltgKknPs6rS6jchLIlxaURCt5GWIBk-LGDxYdlJKtbYMok78YRcsnEkRQnIENM5GaLVY0NcX7U4vbUEFIudQmQflnu5xY0eFk9G9yU4dX9eVJ9_3T-7exLffn188XZ6WXtGyNK3XU9VUpR0Nw3svNdO3gvZaOVk9D3Wio9eNXI1nDupWGad0Y0ojeia4yhgzipPh581103Q-9hKclNdk1hdunWRhfsY2UJWzvGayu1kY2iaPDu3iBF3CwXO4fsYZrwP-IuW2Y4ooK1BtG3_6BXcZcWXM9yyoXQTMoWqfcHyqeYc4Lh4TGM2n3UFqO2-6gtRo34m78XeIB_Z4tAfQAySssI6c_U_xreAVbOtuM</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2023381557</pqid></control><display><type>article</type><title>Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>ProQuest Central UK/Ireland</source><source>Alma/SFX Local Collection</source><creator>Lionel, Anath C ; Costain, Gregory ; Monfared, Nasim ; Walker, Susan ; Reuter, Miriam S ; Hosseini, S Mohsen ; Thiruvahindrapuram, Bhooma ; Merico, Daniele ; Jobling, Rebekah ; Nalpathamkalam, Thomas ; Pellecchia, Giovanna ; Sung, Wilson W L ; Wang, Zhuozhi ; Bikangaga, Peter ; Boelman, Cyrus ; Carter, Melissa T ; Cordeiro, Dawn ; Cytrynbaum, Cheryl ; Dell, Sharon D ; Dhir, Priya ; Dowling, James J ; Heon, Elise ; Hewson, Stacy ; Hiraki, Linda ; Inbar-Feigenberg, Michal ; Klatt, Regan ; Kronick, Jonathan ; Laxer, Ronald M ; Licht, Christoph ; MacDonald, Heather ; Mercimek-Andrews, Saadet ; Mendoza-Londono, Roberto ; Piscione, Tino ; Schneider, Rayfel ; Schulze, Andreas ; Silverman, Earl ; Siriwardena, Komudi ; Snead, O Carter ; Sondheimer, Neal ; Sutherland, Joanne ; Vincent, Ajoy ; Wasserman, Jonathan D ; Weksberg, Rosanna ; Shuman, Cheryl ; Carew, Chris ; Szego, Michael J ; Hayeems, Robin Z ; Basran, Raveen ; Stavropoulos, Dimitri J ; Ray, Peter N ; Bowdin, Sarah ; Meyn, M Stephen ; Cohn, Ronald D ; Scherer, Stephen W ; Marshall, Christian R</creator><creatorcontrib>Lionel, Anath C ; Costain, Gregory ; Monfared, Nasim ; Walker, Susan ; Reuter, Miriam S ; Hosseini, S Mohsen ; Thiruvahindrapuram, Bhooma ; Merico, Daniele ; Jobling, Rebekah ; Nalpathamkalam, Thomas ; Pellecchia, Giovanna ; Sung, Wilson W L ; Wang, Zhuozhi ; Bikangaga, Peter ; Boelman, Cyrus ; Carter, Melissa T ; Cordeiro, Dawn ; Cytrynbaum, Cheryl ; Dell, Sharon D ; Dhir, Priya ; Dowling, James J ; Heon, Elise ; Hewson, Stacy ; Hiraki, Linda ; Inbar-Feigenberg, Michal ; Klatt, Regan ; Kronick, Jonathan ; Laxer, Ronald M ; Licht, Christoph ; MacDonald, Heather ; Mercimek-Andrews, Saadet ; Mendoza-Londono, Roberto ; Piscione, Tino ; Schneider, Rayfel ; Schulze, Andreas ; Silverman, Earl ; Siriwardena, Komudi ; Snead, O Carter ; Sondheimer, Neal ; Sutherland, Joanne ; Vincent, Ajoy ; Wasserman, Jonathan D ; Weksberg, Rosanna ; Shuman, Cheryl ; Carew, Chris ; Szego, Michael J ; Hayeems, Robin Z ; Basran, Raveen ; Stavropoulos, Dimitri J ; Ray, Peter N ; Bowdin, Sarah ; Meyn, M Stephen ; Cohn, Ronald D ; Scherer, Stephen W ; Marshall, Christian R</creatorcontrib><description>Purpose
Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.
Methods
We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.
Results
WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%;
P
= 0.01). Genes clinically sequenced in the cohort (
n
= 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes
PIGG
,
RNU4ATAC
,
TRIO
, and
UNC13A
.
Conclusion
WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.</description><identifier>ISSN: 1098-3600</identifier><identifier>EISSN: 1530-0366</identifier><identifier>DOI: 10.1038/gim.2017.119</identifier><identifier>PMID: 28771251</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208/514/2254 ; 631/208/726/649/2157 ; 692/700/139/1512 ; Biomedical and Life Sciences ; Biomedicine ; Computational Biology - methods ; DNA Copy Number Variations ; Exome ; Female ; Genes ; Genetic Association Studies - methods ; Genetic Association Studies - standards ; Genetic Diseases, Inborn - diagnosis ; Genetic Diseases, Inborn - genetics ; Genetic Predisposition to Disease ; Genetic Testing - methods ; Genetic Testing - standards ; Genetic Variation ; Genomes ; Human Genetics ; Humans ; Laboratory Medicine ; Male ; Molecular Sequence Annotation ; Original ; original-research-article ; Pediatrics ; Phenotype ; Sequence Analysis, DNA - methods ; Sequence Analysis, DNA - standards ; Whole Exome Sequencing - methods ; Whole Exome Sequencing - standards ; Whole Genome Sequencing - methods ; Whole Genome Sequencing - standards</subject><ispartof>Genetics in medicine, 2018-04, Vol.20 (4), p.435-443</ispartof><rights>The Author(s) 2018</rights><rights>Copyright Nature Publishing Group Apr 2018</rights><rights>Copyright © 2018 The Author(s) 2018 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c493t-bbd06660e82c45bcb7fcc55486a5edd8568fc6457922c59182b9343d93b4990f3</citedby><cites>FETCH-LOGICAL-c493t-bbd06660e82c45bcb7fcc55486a5edd8568fc6457922c59182b9343d93b4990f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2023381557?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,777,781,882,27905,27906,64364,64366,64368,72218</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28771251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lionel, Anath C</creatorcontrib><creatorcontrib>Costain, Gregory</creatorcontrib><creatorcontrib>Monfared, Nasim</creatorcontrib><creatorcontrib>Walker, Susan</creatorcontrib><creatorcontrib>Reuter, Miriam S</creatorcontrib><creatorcontrib>Hosseini, S Mohsen</creatorcontrib><creatorcontrib>Thiruvahindrapuram, Bhooma</creatorcontrib><creatorcontrib>Merico, Daniele</creatorcontrib><creatorcontrib>Jobling, Rebekah</creatorcontrib><creatorcontrib>Nalpathamkalam, Thomas</creatorcontrib><creatorcontrib>Pellecchia, Giovanna</creatorcontrib><creatorcontrib>Sung, Wilson W L</creatorcontrib><creatorcontrib>Wang, Zhuozhi</creatorcontrib><creatorcontrib>Bikangaga, Peter</creatorcontrib><creatorcontrib>Boelman, Cyrus</creatorcontrib><creatorcontrib>Carter, Melissa T</creatorcontrib><creatorcontrib>Cordeiro, Dawn</creatorcontrib><creatorcontrib>Cytrynbaum, Cheryl</creatorcontrib><creatorcontrib>Dell, Sharon D</creatorcontrib><creatorcontrib>Dhir, Priya</creatorcontrib><creatorcontrib>Dowling, James J</creatorcontrib><creatorcontrib>Heon, Elise</creatorcontrib><creatorcontrib>Hewson, Stacy</creatorcontrib><creatorcontrib>Hiraki, Linda</creatorcontrib><creatorcontrib>Inbar-Feigenberg, Michal</creatorcontrib><creatorcontrib>Klatt, Regan</creatorcontrib><creatorcontrib>Kronick, Jonathan</creatorcontrib><creatorcontrib>Laxer, Ronald M</creatorcontrib><creatorcontrib>Licht, Christoph</creatorcontrib><creatorcontrib>MacDonald, Heather</creatorcontrib><creatorcontrib>Mercimek-Andrews, Saadet</creatorcontrib><creatorcontrib>Mendoza-Londono, Roberto</creatorcontrib><creatorcontrib>Piscione, Tino</creatorcontrib><creatorcontrib>Schneider, Rayfel</creatorcontrib><creatorcontrib>Schulze, Andreas</creatorcontrib><creatorcontrib>Silverman, Earl</creatorcontrib><creatorcontrib>Siriwardena, Komudi</creatorcontrib><creatorcontrib>Snead, O Carter</creatorcontrib><creatorcontrib>Sondheimer, Neal</creatorcontrib><creatorcontrib>Sutherland, Joanne</creatorcontrib><creatorcontrib>Vincent, Ajoy</creatorcontrib><creatorcontrib>Wasserman, Jonathan D</creatorcontrib><creatorcontrib>Weksberg, Rosanna</creatorcontrib><creatorcontrib>Shuman, Cheryl</creatorcontrib><creatorcontrib>Carew, Chris</creatorcontrib><creatorcontrib>Szego, Michael J</creatorcontrib><creatorcontrib>Hayeems, Robin Z</creatorcontrib><creatorcontrib>Basran, Raveen</creatorcontrib><creatorcontrib>Stavropoulos, Dimitri J</creatorcontrib><creatorcontrib>Ray, Peter N</creatorcontrib><creatorcontrib>Bowdin, Sarah</creatorcontrib><creatorcontrib>Meyn, M Stephen</creatorcontrib><creatorcontrib>Cohn, Ronald D</creatorcontrib><creatorcontrib>Scherer, Stephen W</creatorcontrib><creatorcontrib>Marshall, Christian R</creatorcontrib><title>Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test</title><title>Genetics in medicine</title><addtitle>Genet Med</addtitle><addtitle>Genet Med</addtitle><description>Purpose
Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.
Methods
We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.
Results
WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%;
P
= 0.01). Genes clinically sequenced in the cohort (
n
= 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes
PIGG
,
RNU4ATAC
,
TRIO
, and
UNC13A
.
Conclusion
WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.</description><subject>631/208/514/2254</subject><subject>631/208/726/649/2157</subject><subject>692/700/139/1512</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Computational Biology - methods</subject><subject>DNA Copy Number Variations</subject><subject>Exome</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic Association Studies - methods</subject><subject>Genetic Association Studies - standards</subject><subject>Genetic Diseases, Inborn - diagnosis</subject><subject>Genetic Diseases, Inborn - genetics</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Testing - methods</subject><subject>Genetic Testing - standards</subject><subject>Genetic Variation</subject><subject>Genomes</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Laboratory Medicine</subject><subject>Male</subject><subject>Molecular Sequence Annotation</subject><subject>Original</subject><subject>original-research-article</subject><subject>Pediatrics</subject><subject>Phenotype</subject><subject>Sequence Analysis, DNA - methods</subject><subject>Sequence Analysis, DNA - standards</subject><subject>Whole Exome Sequencing - methods</subject><subject>Whole Exome Sequencing - standards</subject><subject>Whole Genome Sequencing - methods</subject><subject>Whole Genome Sequencing - standards</subject><issn>1098-3600</issn><issn>1530-0366</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNptkU9v1DAQxSMEoqVw44wsceFAFv-JHfuCVFUFKlXiAmfLcSZZV0kcbG-rfgs-cmfZUiji5LHeb954_KrqNaMbRoX-MIZ5wylrN4yZJ9Uxk4LWVCj1FGtqdC0UpUfVi5yvKFKC0-fVEddty7hkx9XPi3lN8Rp60gc3LjGX4MltgKknPs6rS6jchLIlxaURCt5GWIBk-LGDxYdlJKtbYMok78YRcsnEkRQnIENM5GaLVY0NcX7U4vbUEFIudQmQflnu5xY0eFk9G9yU4dX9eVJ9_3T-7exLffn188XZ6WXtGyNK3XU9VUpR0Nw3svNdO3gvZaOVk9D3Wio9eNXI1nDupWGad0Y0ojeia4yhgzipPh581103Q-9hKclNdk1hdunWRhfsY2UJWzvGayu1kY2iaPDu3iBF3CwXO4fsYZrwP-IuW2Y4ooK1BtG3_6BXcZcWXM9yyoXQTMoWqfcHyqeYc4Lh4TGM2n3UFqO2-6gtRo34m78XeIB_Z4tAfQAySssI6c_U_xreAVbOtuM</recordid><startdate>20180401</startdate><enddate>20180401</enddate><creator>Lionel, Anath C</creator><creator>Costain, Gregory</creator><creator>Monfared, Nasim</creator><creator>Walker, Susan</creator><creator>Reuter, Miriam S</creator><creator>Hosseini, S Mohsen</creator><creator>Thiruvahindrapuram, Bhooma</creator><creator>Merico, Daniele</creator><creator>Jobling, Rebekah</creator><creator>Nalpathamkalam, Thomas</creator><creator>Pellecchia, Giovanna</creator><creator>Sung, Wilson W L</creator><creator>Wang, Zhuozhi</creator><creator>Bikangaga, Peter</creator><creator>Boelman, Cyrus</creator><creator>Carter, Melissa T</creator><creator>Cordeiro, Dawn</creator><creator>Cytrynbaum, Cheryl</creator><creator>Dell, Sharon D</creator><creator>Dhir, Priya</creator><creator>Dowling, James J</creator><creator>Heon, Elise</creator><creator>Hewson, Stacy</creator><creator>Hiraki, Linda</creator><creator>Inbar-Feigenberg, Michal</creator><creator>Klatt, Regan</creator><creator>Kronick, Jonathan</creator><creator>Laxer, Ronald M</creator><creator>Licht, Christoph</creator><creator>MacDonald, Heather</creator><creator>Mercimek-Andrews, Saadet</creator><creator>Mendoza-Londono, Roberto</creator><creator>Piscione, Tino</creator><creator>Schneider, Rayfel</creator><creator>Schulze, Andreas</creator><creator>Silverman, Earl</creator><creator>Siriwardena, Komudi</creator><creator>Snead, O Carter</creator><creator>Sondheimer, Neal</creator><creator>Sutherland, Joanne</creator><creator>Vincent, Ajoy</creator><creator>Wasserman, Jonathan D</creator><creator>Weksberg, Rosanna</creator><creator>Shuman, Cheryl</creator><creator>Carew, Chris</creator><creator>Szego, Michael J</creator><creator>Hayeems, Robin Z</creator><creator>Basran, Raveen</creator><creator>Stavropoulos, Dimitri J</creator><creator>Ray, Peter N</creator><creator>Bowdin, Sarah</creator><creator>Meyn, M Stephen</creator><creator>Cohn, Ronald D</creator><creator>Scherer, Stephen W</creator><creator>Marshall, Christian R</creator><general>Nature Publishing Group US</general><general>Elsevier Limited</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180401</creationdate><title>Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test</title><author>Lionel, Anath C ; Costain, Gregory ; Monfared, Nasim ; Walker, Susan ; Reuter, Miriam S ; Hosseini, S Mohsen ; Thiruvahindrapuram, Bhooma ; Merico, Daniele ; Jobling, Rebekah ; Nalpathamkalam, Thomas ; Pellecchia, Giovanna ; Sung, Wilson W L ; Wang, Zhuozhi ; Bikangaga, Peter ; Boelman, Cyrus ; Carter, Melissa T ; Cordeiro, Dawn ; Cytrynbaum, Cheryl ; Dell, Sharon D ; Dhir, Priya ; Dowling, James J ; Heon, Elise ; Hewson, Stacy ; Hiraki, Linda ; Inbar-Feigenberg, Michal ; Klatt, Regan ; Kronick, Jonathan ; Laxer, Ronald M ; Licht, Christoph ; MacDonald, Heather ; Mercimek-Andrews, Saadet ; Mendoza-Londono, Roberto ; Piscione, Tino ; Schneider, Rayfel ; Schulze, Andreas ; Silverman, Earl ; Siriwardena, Komudi ; Snead, O Carter ; Sondheimer, Neal ; Sutherland, Joanne ; Vincent, Ajoy ; Wasserman, Jonathan D ; Weksberg, Rosanna ; Shuman, Cheryl ; Carew, Chris ; Szego, Michael J ; Hayeems, Robin Z ; Basran, Raveen ; Stavropoulos, Dimitri J ; Ray, Peter N ; Bowdin, Sarah ; Meyn, M Stephen ; Cohn, Ronald D ; Scherer, Stephen W ; Marshall, Christian R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-bbd06660e82c45bcb7fcc55486a5edd8568fc6457922c59182b9343d93b4990f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>631/208/514/2254</topic><topic>631/208/726/649/2157</topic><topic>692/700/139/1512</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Computational Biology - methods</topic><topic>DNA Copy Number Variations</topic><topic>Exome</topic><topic>Female</topic><topic>Genes</topic><topic>Genetic Association Studies - methods</topic><topic>Genetic Association Studies - standards</topic><topic>Genetic Diseases, Inborn - diagnosis</topic><topic>Genetic Diseases, Inborn - genetics</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Testing - methods</topic><topic>Genetic Testing - standards</topic><topic>Genetic Variation</topic><topic>Genomes</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Laboratory Medicine</topic><topic>Male</topic><topic>Molecular Sequence Annotation</topic><topic>Original</topic><topic>original-research-article</topic><topic>Pediatrics</topic><topic>Phenotype</topic><topic>Sequence Analysis, DNA - methods</topic><topic>Sequence Analysis, DNA - standards</topic><topic>Whole Exome Sequencing - methods</topic><topic>Whole Exome Sequencing - standards</topic><topic>Whole Genome Sequencing - methods</topic><topic>Whole Genome Sequencing - standards</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lionel, Anath C</creatorcontrib><creatorcontrib>Costain, Gregory</creatorcontrib><creatorcontrib>Monfared, Nasim</creatorcontrib><creatorcontrib>Walker, Susan</creatorcontrib><creatorcontrib>Reuter, Miriam S</creatorcontrib><creatorcontrib>Hosseini, S Mohsen</creatorcontrib><creatorcontrib>Thiruvahindrapuram, Bhooma</creatorcontrib><creatorcontrib>Merico, Daniele</creatorcontrib><creatorcontrib>Jobling, Rebekah</creatorcontrib><creatorcontrib>Nalpathamkalam, Thomas</creatorcontrib><creatorcontrib>Pellecchia, Giovanna</creatorcontrib><creatorcontrib>Sung, Wilson W L</creatorcontrib><creatorcontrib>Wang, Zhuozhi</creatorcontrib><creatorcontrib>Bikangaga, Peter</creatorcontrib><creatorcontrib>Boelman, Cyrus</creatorcontrib><creatorcontrib>Carter, Melissa T</creatorcontrib><creatorcontrib>Cordeiro, Dawn</creatorcontrib><creatorcontrib>Cytrynbaum, Cheryl</creatorcontrib><creatorcontrib>Dell, Sharon D</creatorcontrib><creatorcontrib>Dhir, Priya</creatorcontrib><creatorcontrib>Dowling, James J</creatorcontrib><creatorcontrib>Heon, Elise</creatorcontrib><creatorcontrib>Hewson, Stacy</creatorcontrib><creatorcontrib>Hiraki, Linda</creatorcontrib><creatorcontrib>Inbar-Feigenberg, Michal</creatorcontrib><creatorcontrib>Klatt, Regan</creatorcontrib><creatorcontrib>Kronick, Jonathan</creatorcontrib><creatorcontrib>Laxer, Ronald M</creatorcontrib><creatorcontrib>Licht, Christoph</creatorcontrib><creatorcontrib>MacDonald, Heather</creatorcontrib><creatorcontrib>Mercimek-Andrews, Saadet</creatorcontrib><creatorcontrib>Mendoza-Londono, Roberto</creatorcontrib><creatorcontrib>Piscione, Tino</creatorcontrib><creatorcontrib>Schneider, Rayfel</creatorcontrib><creatorcontrib>Schulze, Andreas</creatorcontrib><creatorcontrib>Silverman, Earl</creatorcontrib><creatorcontrib>Siriwardena, Komudi</creatorcontrib><creatorcontrib>Snead, O Carter</creatorcontrib><creatorcontrib>Sondheimer, Neal</creatorcontrib><creatorcontrib>Sutherland, Joanne</creatorcontrib><creatorcontrib>Vincent, Ajoy</creatorcontrib><creatorcontrib>Wasserman, Jonathan D</creatorcontrib><creatorcontrib>Weksberg, Rosanna</creatorcontrib><creatorcontrib>Shuman, Cheryl</creatorcontrib><creatorcontrib>Carew, Chris</creatorcontrib><creatorcontrib>Szego, Michael J</creatorcontrib><creatorcontrib>Hayeems, Robin Z</creatorcontrib><creatorcontrib>Basran, Raveen</creatorcontrib><creatorcontrib>Stavropoulos, Dimitri J</creatorcontrib><creatorcontrib>Ray, Peter N</creatorcontrib><creatorcontrib>Bowdin, Sarah</creatorcontrib><creatorcontrib>Meyn, M Stephen</creatorcontrib><creatorcontrib>Cohn, Ronald D</creatorcontrib><creatorcontrib>Scherer, Stephen W</creatorcontrib><creatorcontrib>Marshall, Christian R</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genetics in medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lionel, Anath C</au><au>Costain, Gregory</au><au>Monfared, Nasim</au><au>Walker, Susan</au><au>Reuter, Miriam S</au><au>Hosseini, S Mohsen</au><au>Thiruvahindrapuram, Bhooma</au><au>Merico, Daniele</au><au>Jobling, Rebekah</au><au>Nalpathamkalam, Thomas</au><au>Pellecchia, Giovanna</au><au>Sung, Wilson W L</au><au>Wang, Zhuozhi</au><au>Bikangaga, Peter</au><au>Boelman, Cyrus</au><au>Carter, Melissa T</au><au>Cordeiro, Dawn</au><au>Cytrynbaum, Cheryl</au><au>Dell, Sharon D</au><au>Dhir, Priya</au><au>Dowling, James J</au><au>Heon, Elise</au><au>Hewson, Stacy</au><au>Hiraki, Linda</au><au>Inbar-Feigenberg, Michal</au><au>Klatt, Regan</au><au>Kronick, Jonathan</au><au>Laxer, Ronald M</au><au>Licht, Christoph</au><au>MacDonald, Heather</au><au>Mercimek-Andrews, Saadet</au><au>Mendoza-Londono, Roberto</au><au>Piscione, Tino</au><au>Schneider, Rayfel</au><au>Schulze, Andreas</au><au>Silverman, Earl</au><au>Siriwardena, Komudi</au><au>Snead, O Carter</au><au>Sondheimer, Neal</au><au>Sutherland, Joanne</au><au>Vincent, Ajoy</au><au>Wasserman, Jonathan D</au><au>Weksberg, Rosanna</au><au>Shuman, Cheryl</au><au>Carew, Chris</au><au>Szego, Michael J</au><au>Hayeems, Robin Z</au><au>Basran, Raveen</au><au>Stavropoulos, Dimitri J</au><au>Ray, Peter N</au><au>Bowdin, Sarah</au><au>Meyn, M Stephen</au><au>Cohn, Ronald D</au><au>Scherer, Stephen W</au><au>Marshall, Christian R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test</atitle><jtitle>Genetics in medicine</jtitle><stitle>Genet Med</stitle><addtitle>Genet Med</addtitle><date>2018-04-01</date><risdate>2018</risdate><volume>20</volume><issue>4</issue><spage>435</spage><epage>443</epage><pages>435-443</pages><issn>1098-3600</issn><eissn>1530-0366</eissn><abstract>Purpose
Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.
Methods
We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.
Results
WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%;
P
= 0.01). Genes clinically sequenced in the cohort (
n
= 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes
PIGG
,
RNU4ATAC
,
TRIO
, and
UNC13A
.
Conclusion
WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>28771251</pmid><doi>10.1038/gim.2017.119</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1098-3600 |
| ispartof | Genetics in medicine, 2018-04, Vol.20 (4), p.435-443 |
| issn | 1098-3600 1530-0366 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5895460 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | 631/208/514/2254 631/208/726/649/2157 692/700/139/1512 Biomedical and Life Sciences Biomedicine Computational Biology - methods DNA Copy Number Variations Exome Female Genes Genetic Association Studies - methods Genetic Association Studies - standards Genetic Diseases, Inborn - diagnosis Genetic Diseases, Inborn - genetics Genetic Predisposition to Disease Genetic Testing - methods Genetic Testing - standards Genetic Variation Genomes Human Genetics Humans Laboratory Medicine Male Molecular Sequence Annotation Original original-research-article Pediatrics Phenotype Sequence Analysis, DNA - methods Sequence Analysis, DNA - standards Whole Exome Sequencing - methods Whole Exome Sequencing - standards Whole Genome Sequencing - methods Whole Genome Sequencing - standards |
| title | Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T04%3A55%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Improved%20diagnostic%20yield%20compared%20with%20targeted%20gene%20sequencing%20panels%20suggests%20a%20role%20for%20whole-genome%20sequencing%20as%20a%20first-tier%20genetic%20test&rft.jtitle=Genetics%20in%20medicine&rft.au=Lionel,%20Anath%20C&rft.date=2018-04-01&rft.volume=20&rft.issue=4&rft.spage=435&rft.epage=443&rft.pages=435-443&rft.issn=1098-3600&rft.eissn=1530-0366&rft_id=info:doi/10.1038/gim.2017.119&rft_dat=%3Cproquest_pubme%3E2023381557%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2023381557&rft_id=info:pmid/28771251&rfr_iscdi=true |