Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma
Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical imple...
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| Veröffentlicht in: | American journal of human genetics 2003-02, Vol.72 (2), p.253-269 |
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| container_title | American journal of human genetics |
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| creator | Richter, Suzanne Vandezande, Kirk Chen, Ning Zhang, Katherine Sutherland, Joanne Anderson, Julie Han, Liping Panton, Rachel Branco, Patricia Gallie, Brenda |
| description | Timely molecular diagnosis of
RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of
RB1 mutations are unique and distributed throughout the
RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify
RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to |
| doi_str_mv | 10.1086/345651 |
| format | Article |
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RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of
RB1 mutations are unique and distributed throughout the
RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify
RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1086/345651</identifier><identifier>PMID: 12541220</identifier><identifier>CODEN: AJHGAG</identifier><language>eng</language><publisher>Chicago, IL: Elsevier Inc</publisher><subject>Algorithms ; Biological and medical sciences ; DNA - analysis ; DNA - economics ; DNA - genetics ; DNA Methylation ; DNA Mutational Analysis ; DNA, Neoplasm - analysis ; DNA, Neoplasm - genetics ; Genes, Retinoblastoma ; Genotype ; Humans ; Leukocytes, Mononuclear - chemistry ; Medical sciences ; Mutation ; Ophthalmology ; Pedigree ; Phenotype ; Population Surveillance ; Retinoblastoma - genetics ; Sensitivity and Specificity ; Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus</subject><ispartof>American journal of human genetics, 2003-02, Vol.72 (2), p.253-269</ispartof><rights>2003 The American Society of Human Genetics</rights><rights>2003 INIST-CNRS</rights><rights>2003 by The American Society of Human Genetics. All rights reserved. 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432t-c8034c506e16658e53718ba4a5c686ddf158ff3086e6e2622d1ede2f211bd61f3</citedby><cites>FETCH-LOGICAL-c432t-c8034c506e16658e53718ba4a5c686ddf158ff3086e6e2622d1ede2f211bd61f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC379221/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1086/345651$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3550,27924,27925,45995,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14536715$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12541220$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Richter, Suzanne</creatorcontrib><creatorcontrib>Vandezande, Kirk</creatorcontrib><creatorcontrib>Chen, Ning</creatorcontrib><creatorcontrib>Zhang, Katherine</creatorcontrib><creatorcontrib>Sutherland, Joanne</creatorcontrib><creatorcontrib>Anderson, Julie</creatorcontrib><creatorcontrib>Han, Liping</creatorcontrib><creatorcontrib>Panton, Rachel</creatorcontrib><creatorcontrib>Branco, Patricia</creatorcontrib><creatorcontrib>Gallie, Brenda</creatorcontrib><title>Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>Timely molecular diagnosis of
RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of
RB1 mutations are unique and distributed throughout the
RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify
RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations.</description><subject>Algorithms</subject><subject>Biological and medical sciences</subject><subject>DNA - analysis</subject><subject>DNA - economics</subject><subject>DNA - genetics</subject><subject>DNA Methylation</subject><subject>DNA Mutational Analysis</subject><subject>DNA, Neoplasm - analysis</subject><subject>DNA, Neoplasm - genetics</subject><subject>Genes, Retinoblastoma</subject><subject>Genotype</subject><subject>Humans</subject><subject>Leukocytes, Mononuclear - chemistry</subject><subject>Medical sciences</subject><subject>Mutation</subject><subject>Ophthalmology</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Population Surveillance</subject><subject>Retinoblastoma - genetics</subject><subject>Sensitivity and Specificity</subject><subject>Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFvEzEQhS1ERdMAPwH5ArdtPd61d3PgQENaKhUhFThbjj0mRrt2sZ1U_HscJWqBk6XxNzPvzSPkNbBzYIO8aDshBTwjMxBt30jJxHMyY4zxZsEX_Sk5y_knYwADa1-QU-CiA87ZjLivGLIvfodUB0tXznnjMRT6EQua4mOg0dG7S6DXGJB-3ha9L2a6ChsdDGa61Ampi4le6cmPvlYefNnQOyw-xPWoc4mTfklOnB4zvjq-c_L9avVt-am5_XJ9s_xw25iu5aUxVV5nBJMIUooBqxcY1rrTwshBWutADM611TBK5JJzC2iROw6wthJcOyfvD3Pvt-sJralOkh7VffKTTr9V1F79-xP8Rv2IO9X2C86h9r879qf4a4u5qMlng-OoA8ZtVn09JpdV5SNoUsw5oXvcAUztE1GHRCr45m9FT9gxggq8PQI6Gz26VM_q8xPXiVb2NdU5YQcO6_12HpPK-6QMWp9qUspG___uPzLFo2Q</recordid><startdate>20030201</startdate><enddate>20030201</enddate><creator>Richter, Suzanne</creator><creator>Vandezande, Kirk</creator><creator>Chen, Ning</creator><creator>Zhang, Katherine</creator><creator>Sutherland, Joanne</creator><creator>Anderson, Julie</creator><creator>Han, Liping</creator><creator>Panton, Rachel</creator><creator>Branco, Patricia</creator><creator>Gallie, Brenda</creator><general>Elsevier Inc</general><general>University of Chicago Press</general><general>The American Society of Human Genetics</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20030201</creationdate><title>Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma</title><author>Richter, Suzanne ; Vandezande, Kirk ; Chen, Ning ; Zhang, Katherine ; Sutherland, Joanne ; Anderson, Julie ; Han, Liping ; Panton, Rachel ; Branco, Patricia ; Gallie, Brenda</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432t-c8034c506e16658e53718ba4a5c686ddf158ff3086e6e2622d1ede2f211bd61f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Algorithms</topic><topic>Biological and medical sciences</topic><topic>DNA - analysis</topic><topic>DNA - economics</topic><topic>DNA - genetics</topic><topic>DNA Methylation</topic><topic>DNA Mutational Analysis</topic><topic>DNA, Neoplasm - analysis</topic><topic>DNA, Neoplasm - genetics</topic><topic>Genes, Retinoblastoma</topic><topic>Genotype</topic><topic>Humans</topic><topic>Leukocytes, Mononuclear - chemistry</topic><topic>Medical sciences</topic><topic>Mutation</topic><topic>Ophthalmology</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Population Surveillance</topic><topic>Retinoblastoma - genetics</topic><topic>Sensitivity and Specificity</topic><topic>Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Richter, Suzanne</creatorcontrib><creatorcontrib>Vandezande, Kirk</creatorcontrib><creatorcontrib>Chen, Ning</creatorcontrib><creatorcontrib>Zhang, Katherine</creatorcontrib><creatorcontrib>Sutherland, Joanne</creatorcontrib><creatorcontrib>Anderson, Julie</creatorcontrib><creatorcontrib>Han, Liping</creatorcontrib><creatorcontrib>Panton, Rachel</creatorcontrib><creatorcontrib>Branco, Patricia</creatorcontrib><creatorcontrib>Gallie, Brenda</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Richter, Suzanne</au><au>Vandezande, Kirk</au><au>Chen, Ning</au><au>Zhang, Katherine</au><au>Sutherland, Joanne</au><au>Anderson, Julie</au><au>Han, Liping</au><au>Panton, Rachel</au><au>Branco, Patricia</au><au>Gallie, Brenda</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>2003-02-01</date><risdate>2003</risdate><volume>72</volume><issue>2</issue><spage>253</spage><epage>269</epage><pages>253-269</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><coden>AJHGAG</coden><abstract>Timely molecular diagnosis of
RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of
RB1 mutations are unique and distributed throughout the
RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify
RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations.</abstract><cop>Chicago, IL</cop><pub>Elsevier Inc</pub><pmid>12541220</pmid><doi>10.1086/345651</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Algorithms Biological and medical sciences DNA - analysis DNA - economics DNA - genetics DNA Methylation DNA Mutational Analysis DNA, Neoplasm - analysis DNA, Neoplasm - genetics Genes, Retinoblastoma Genotype Humans Leukocytes, Mononuclear - chemistry Medical sciences Mutation Ophthalmology Pedigree Phenotype Population Surveillance Retinoblastoma - genetics Sensitivity and Specificity Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus |
| title | Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma |
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