Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity
Identifieur interne : 002E26 ( Pmc/Corpus ); précédent : 002E25; suivant : 002E27Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity
Auteurs : Michael Y. Zhang ; Siobán B. Keel ; Tom Walsh ; Ming K. Lee ; Suleyman Gulsuner ; Amanda C. Watts ; Colin C. Pritchard ; Stephen J. Salipante ; Michael R. Jeng ; Inga Hofmann ; David A. Williams ; Mark D. Fleming ; Janis L. Abkowitz ; Mary-Claire King ; Akiko ShimamuraSource :
- Haematologica [ 0390-6078 ] ; 2015.
Abstract
Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in
Url:
DOI: 10.3324/haematol.2014.113456
PubMed: 25239263
PubMed Central: 4281311
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PMC:4281311Le document en format XML
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<author><name sortKey="Zhang, Michael Y" sort="Zhang, Michael Y" uniqKey="Zhang M" first="Michael Y." last="Zhang">Michael Y. Zhang</name>
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<author><name sortKey="Walsh, Tom" sort="Walsh, Tom" uniqKey="Walsh T" first="Tom" last="Walsh">Tom Walsh</name>
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<author><name sortKey="Watts, Amanda C" sort="Watts, Amanda C" uniqKey="Watts A" first="Amanda C." last="Watts">Amanda C. Watts</name>
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<author><name sortKey="Jeng, Michael R" sort="Jeng, Michael R" uniqKey="Jeng M" first="Michael R." last="Jeng">Michael R. Jeng</name>
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</affiliation>
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<author><name sortKey="Hofmann, Inga" sort="Hofmann, Inga" uniqKey="Hofmann I" first="Inga" last="Hofmann">Inga Hofmann</name>
<affiliation><nlm:aff id="af6-1000042">Division of Hematology/Oncology, Boston Children’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA</nlm:aff>
</affiliation>
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<author><name sortKey="Williams, David A" sort="Williams, David A" uniqKey="Williams D" first="David A." last="Williams">David A. Williams</name>
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</affiliation>
<affiliation><nlm:aff id="af7-1000042">Harvard Stem Cell Institute, Boston, MA</nlm:aff>
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<author><name sortKey="Fleming, Mark D" sort="Fleming, Mark D" uniqKey="Fleming M" first="Mark D." last="Fleming">Mark D. Fleming</name>
<affiliation><nlm:aff id="af8-1000042">Department of Pathology, Boston Children’s Hospital, MA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Abkowitz, Janis L" sort="Abkowitz, Janis L" uniqKey="Abkowitz J" first="Janis L." last="Abkowitz">Janis L. Abkowitz</name>
<affiliation><nlm:aff id="af2-1000042">Department of Medicine, Division of Hematology, University of Washington, Seattle, WA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="King, Mary Claire" sort="King, Mary Claire" uniqKey="King M" first="Mary-Claire" last="King">Mary-Claire King</name>
<affiliation><nlm:aff id="af3-1000042">Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shimamura, Akiko" sort="Shimamura, Akiko" uniqKey="Shimamura A" first="Akiko" last="Shimamura">Akiko Shimamura</name>
<affiliation><nlm:aff id="af1-1000042">Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="af9-1000042">Department of Pediatric Hematology/Oncology, Seattle Children’s Hospital, WA</nlm:aff>
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<affiliation><nlm:aff id="af10-1000042">Department of Pediatrics, University of Washington, Seattle, WA, USA</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity</title>
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<author><name sortKey="Keel, Sioban B" sort="Keel, Sioban B" uniqKey="Keel S" first="Siobán B." last="Keel">Siobán B. Keel</name>
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<author><name sortKey="Walsh, Tom" sort="Walsh, Tom" uniqKey="Walsh T" first="Tom" last="Walsh">Tom Walsh</name>
<affiliation><nlm:aff id="af3-1000042">Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA</nlm:aff>
</affiliation>
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<author><name sortKey="Lee, Ming K" sort="Lee, Ming K" uniqKey="Lee M" first="Ming K." last="Lee">Ming K. Lee</name>
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<author><name sortKey="Watts, Amanda C" sort="Watts, Amanda C" uniqKey="Watts A" first="Amanda C." last="Watts">Amanda C. Watts</name>
<affiliation><nlm:aff id="af3-1000042">Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA</nlm:aff>
</affiliation>
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<author><name sortKey="Pritchard, Colin C" sort="Pritchard, Colin C" uniqKey="Pritchard C" first="Colin C." last="Pritchard">Colin C. Pritchard</name>
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<author><name sortKey="Salipante, Stephen J" sort="Salipante, Stephen J" uniqKey="Salipante S" first="Stephen J." last="Salipante">Stephen J. Salipante</name>
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</affiliation>
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<author><name sortKey="Jeng, Michael R" sort="Jeng, Michael R" uniqKey="Jeng M" first="Michael R." last="Jeng">Michael R. Jeng</name>
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</affiliation>
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<author><name sortKey="Hofmann, Inga" sort="Hofmann, Inga" uniqKey="Hofmann I" first="Inga" last="Hofmann">Inga Hofmann</name>
<affiliation><nlm:aff id="af6-1000042">Division of Hematology/Oncology, Boston Children’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA</nlm:aff>
</affiliation>
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<author><name sortKey="Williams, David A" sort="Williams, David A" uniqKey="Williams D" first="David A." last="Williams">David A. Williams</name>
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</affiliation>
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</affiliation>
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</affiliation>
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<affiliation><nlm:aff id="af2-1000042">Department of Medicine, Division of Hematology, University of Washington, Seattle, WA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="King, Mary Claire" sort="King, Mary Claire" uniqKey="King M" first="Mary-Claire" last="King">Mary-Claire King</name>
<affiliation><nlm:aff id="af3-1000042">Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA</nlm:aff>
</affiliation>
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<author><name sortKey="Shimamura, Akiko" sort="Shimamura, Akiko" uniqKey="Shimamura A" first="Akiko" last="Shimamura">Akiko Shimamura</name>
<affiliation><nlm:aff id="af1-1000042">Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="af9-1000042">Department of Pediatric Hematology/Oncology, Seattle Children’s Hospital, WA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="af10-1000042">Department of Pediatrics, University of Washington, Seattle, WA, USA</nlm:aff>
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<series><title level="j">Haematologica</title>
<idno type="ISSN">0390-6078</idno>
<idno type="eISSN">1592-8721</idno>
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<front><div type="abstract" xml:lang="en"><p>Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in <italic>GATA2, RUNX1, DKC1</italic>
, or <italic>LIG4</italic>
. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Haematologica</journal-id>
<journal-id journal-id-type="iso-abbrev">Haematologica</journal-id>
<journal-id journal-id-type="hwp">haematol</journal-id>
<journal-id journal-id-type="publisher-id">Haematologica</journal-id>
<journal-title-group><journal-title>Haematologica</journal-title>
</journal-title-group>
<issn pub-type="ppub">0390-6078</issn>
<issn pub-type="epub">1592-8721</issn>
<publisher><publisher-name>Ferrata Storti Foundation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25239263</article-id>
<article-id pub-id-type="pmc">4281311</article-id>
<article-id pub-id-type="doi">10.3324/haematol.2014.113456</article-id>
<article-id pub-id-type="publisher-id">1000042</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Articles</subject>
<subj-group subj-group-type="heading"><subject>Bone Marrow Failure</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Michael Y.</given-names>
</name>
<xref ref-type="aff" rid="af1-1000042">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Keel</surname>
<given-names>Siobán B.</given-names>
</name>
<xref ref-type="aff" rid="af2-1000042">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Walsh</surname>
<given-names>Tom</given-names>
</name>
<xref ref-type="aff" rid="af3-1000042">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Ming K.</given-names>
</name>
<xref ref-type="aff" rid="af3-1000042">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gulsuner</surname>
<given-names>Suleyman</given-names>
</name>
<xref ref-type="aff" rid="af3-1000042">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Watts</surname>
<given-names>Amanda C.</given-names>
</name>
<xref ref-type="aff" rid="af3-1000042">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pritchard</surname>
<given-names>Colin C.</given-names>
</name>
<xref ref-type="aff" rid="af4-1000042">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Salipante</surname>
<given-names>Stephen J.</given-names>
</name>
<xref ref-type="aff" rid="af4-1000042">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jeng</surname>
<given-names>Michael R.</given-names>
</name>
<xref ref-type="aff" rid="af5-1000042">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hofmann</surname>
<given-names>Inga</given-names>
</name>
<xref ref-type="aff" rid="af6-1000042">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Williams</surname>
<given-names>David A.</given-names>
</name>
<xref ref-type="aff" rid="af6-1000042">6</xref>
<xref ref-type="aff" rid="af7-1000042">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fleming</surname>
<given-names>Mark D.</given-names>
</name>
<xref ref-type="aff" rid="af8-1000042">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Abkowitz</surname>
<given-names>Janis L.</given-names>
</name>
<xref ref-type="aff" rid="af2-1000042">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>King</surname>
<given-names>Mary-Claire</given-names>
</name>
<xref ref-type="aff" rid="af3-1000042">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shimamura</surname>
<given-names>Akiko</given-names>
</name>
<xref ref-type="aff" rid="af1-1000042">1</xref>
<xref ref-type="aff" rid="af9-1000042">9</xref>
<xref ref-type="aff" rid="af10-1000042">10</xref>
<xref rid="c1-1000042" ref-type="corresp"></xref>
</contrib>
</contrib-group>
<aff id="af1-1000042"><label>1</label>
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA</aff>
<aff id="af2-1000042"><label>2</label>
Department of Medicine, Division of Hematology, University of Washington, Seattle, WA</aff>
<aff id="af3-1000042"><label>3</label>
Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA</aff>
<aff id="af4-1000042"><label>4</label>
Department of Laboratory Medicine, University of Washington, Seattle, WA</aff>
<aff id="af5-1000042"><label>5</label>
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA</aff>
<aff id="af6-1000042"><label>6</label>
Division of Hematology/Oncology, Boston Children’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA</aff>
<aff id="af7-1000042"><label>7</label>
Harvard Stem Cell Institute, Boston, MA</aff>
<aff id="af8-1000042"><label>8</label>
Department of Pathology, Boston Children’s Hospital, MA</aff>
<aff id="af9-1000042"><label>9</label>
Department of Pediatric Hematology/Oncology, Seattle Children’s Hospital, WA</aff>
<aff id="af10-1000042"><label>10</label>
Department of Pediatrics, University of Washington, Seattle, WA, USA</aff>
<author-notes><corresp id="c1-1000042">Correspondence: <email>ashimamu@fhcrc.org</email>
</corresp>
<fn id="fn1-1000042"><p>M.Y.Z. and S.B.K. contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>1</month>
<year>2015</year>
</pub-date>
<volume>100</volume>
<issue>1</issue>
<fpage>42</fpage>
<lpage>48</lpage>
<history><date date-type="received"><day>22</day>
<month>7</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>15</day>
<month>9</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright© Ferrata Storti Foundation</copyright-statement>
<copyright-year>2015</copyright-year>
</permissions>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="10042.pdf"></self-uri>
<abstract><p>Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in <italic>GATA2, RUNX1, DKC1</italic>
, or <italic>LIG4</italic>
. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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