Lessons learned from additional research analyses of unsolved clinical exome cases
Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for...
Ausführliche Beschreibung
Autor*in: |
Eldomery, Mohammad K. [verfasserIn] |
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E-Artikel |
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Englisch |
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2017 |
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Anmerkung: |
© The Author(s). 2017 |
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Übergeordnetes Werk: |
Enthalten in: Genome medicine - London : BioMed Central, 2009, 9(2017), 1 vom: 21. März |
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Übergeordnetes Werk: |
volume:9 ; year:2017 ; number:1 ; day:21 ; month:03 |
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DOI / URN: |
10.1186/s13073-017-0412-6 |
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SPR030652642 |
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520 | |a Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. | ||
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650 | 4 | |a Molecular Diagnosis |7 (dpeaa)DE-He213 | |
650 | 4 | |a Pathogenic Variant |7 (dpeaa)DE-He213 | |
650 | 4 | |a Single Nucleotide Variant |7 (dpeaa)DE-He213 | |
650 | 4 | |a Whole Exome Sequencing |7 (dpeaa)DE-He213 | |
700 | 1 | |a Coban-Akdemir, Zeynep |4 aut | |
700 | 1 | |a Harel, Tamar |4 aut | |
700 | 1 | |a Rosenfeld, Jill A. |4 aut | |
700 | 1 | |a Gambin, Tomasz |4 aut | |
700 | 1 | |a Stray-Pedersen, Asbjørg |4 aut | |
700 | 1 | |a Küry, Sébastien |4 aut | |
700 | 1 | |a Mercier, Sandra |4 aut | |
700 | 1 | |a Lessel, Davor |4 aut | |
700 | 1 | |a Denecke, Jonas |4 aut | |
700 | 1 | |a Wiszniewski, Wojciech |4 aut | |
700 | 1 | |a Penney, Samantha |4 aut | |
700 | 1 | |a Liu, Pengfei |4 aut | |
700 | 1 | |a Bi, Weimin |4 aut | |
700 | 1 | |a Lalani, Seema R. |4 aut | |
700 | 1 | |a Schaaf, Christian P. |4 aut | |
700 | 1 | |a Wangler, Michael F. |4 aut | |
700 | 1 | |a Bacino, Carlos A. |4 aut | |
700 | 1 | |a Lewis, Richard Alan |4 aut | |
700 | 1 | |a Potocki, Lorraine |4 aut | |
700 | 1 | |a Graham, Brett H. |4 aut | |
700 | 1 | |a Belmont, John W. |4 aut | |
700 | 1 | |a Scaglia, Fernando |4 aut | |
700 | 1 | |a Orange, Jordan S. |4 aut | |
700 | 1 | |a Jhangiani, Shalini N. |4 aut | |
700 | 1 | |a Chiang, Theodore |4 aut | |
700 | 1 | |a Doddapaneni, Harsha |4 aut | |
700 | 1 | |a Hu, Jianhong |4 aut | |
700 | 1 | |a Muzny, Donna M. |4 aut | |
700 | 1 | |a Xia, Fan |4 aut | |
700 | 1 | |a Beaudet, Arthur L. |4 aut | |
700 | 1 | |a Boerwinkle, Eric |4 aut | |
700 | 1 | |a Eng, Christine M. |4 aut | |
700 | 1 | |a Plon, Sharon E. |4 aut | |
700 | 1 | |a Sutton, V. Reid |4 aut | |
700 | 1 | |a Gibbs, Richard A. |4 aut | |
700 | 1 | |a Posey, Jennifer E. |4 aut | |
700 | 1 | |a Yang, Yaping |4 aut | |
700 | 1 | |a Lupski, James R. |4 aut | |
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10.1186/s13073-017-0412-6 doi (DE-627)SPR030652642 (SPR)s13073-017-0412-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut Lessons learned from additional research analyses of unsolved clinical exome cases 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2017 Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. Copy Number Variant (dpeaa)DE-He213 Molecular Diagnosis (dpeaa)DE-He213 Pathogenic Variant (dpeaa)DE-He213 Single Nucleotide Variant (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Coban-Akdemir, Zeynep aut Harel, Tamar aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Stray-Pedersen, Asbjørg aut Küry, Sébastien aut Mercier, Sandra aut Lessel, Davor aut Denecke, Jonas aut Wiszniewski, Wojciech aut Penney, Samantha aut Liu, Pengfei aut Bi, Weimin aut Lalani, Seema R. aut Schaaf, Christian P. aut Wangler, Michael F. aut Bacino, Carlos A. aut Lewis, Richard Alan aut Potocki, Lorraine aut Graham, Brett H. aut Belmont, John W. aut Scaglia, Fernando aut Orange, Jordan S. aut Jhangiani, Shalini N. aut Chiang, Theodore aut Doddapaneni, Harsha aut Hu, Jianhong aut Muzny, Donna M. aut Xia, Fan aut Beaudet, Arthur L. aut Boerwinkle, Eric aut Eng, Christine M. aut Plon, Sharon E. aut Sutton, V. Reid aut Gibbs, Richard A. aut Posey, Jennifer E. aut Yang, Yaping aut Lupski, James R. aut Enthalten in Genome medicine London : BioMed Central, 2009 9(2017), 1 vom: 21. März (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:9 year:2017 number:1 day:21 month:03 https://dx.doi.org/10.1186/s13073-017-0412-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2017 1 21 03 |
spelling |
10.1186/s13073-017-0412-6 doi (DE-627)SPR030652642 (SPR)s13073-017-0412-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut Lessons learned from additional research analyses of unsolved clinical exome cases 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2017 Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. Copy Number Variant (dpeaa)DE-He213 Molecular Diagnosis (dpeaa)DE-He213 Pathogenic Variant (dpeaa)DE-He213 Single Nucleotide Variant (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Coban-Akdemir, Zeynep aut Harel, Tamar aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Stray-Pedersen, Asbjørg aut Küry, Sébastien aut Mercier, Sandra aut Lessel, Davor aut Denecke, Jonas aut Wiszniewski, Wojciech aut Penney, Samantha aut Liu, Pengfei aut Bi, Weimin aut Lalani, Seema R. aut Schaaf, Christian P. aut Wangler, Michael F. aut Bacino, Carlos A. aut Lewis, Richard Alan aut Potocki, Lorraine aut Graham, Brett H. aut Belmont, John W. aut Scaglia, Fernando aut Orange, Jordan S. aut Jhangiani, Shalini N. aut Chiang, Theodore aut Doddapaneni, Harsha aut Hu, Jianhong aut Muzny, Donna M. aut Xia, Fan aut Beaudet, Arthur L. aut Boerwinkle, Eric aut Eng, Christine M. aut Plon, Sharon E. aut Sutton, V. Reid aut Gibbs, Richard A. aut Posey, Jennifer E. aut Yang, Yaping aut Lupski, James R. aut Enthalten in Genome medicine London : BioMed Central, 2009 9(2017), 1 vom: 21. März (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:9 year:2017 number:1 day:21 month:03 https://dx.doi.org/10.1186/s13073-017-0412-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2017 1 21 03 |
allfields_unstemmed |
10.1186/s13073-017-0412-6 doi (DE-627)SPR030652642 (SPR)s13073-017-0412-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut Lessons learned from additional research analyses of unsolved clinical exome cases 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2017 Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. Copy Number Variant (dpeaa)DE-He213 Molecular Diagnosis (dpeaa)DE-He213 Pathogenic Variant (dpeaa)DE-He213 Single Nucleotide Variant (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Coban-Akdemir, Zeynep aut Harel, Tamar aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Stray-Pedersen, Asbjørg aut Küry, Sébastien aut Mercier, Sandra aut Lessel, Davor aut Denecke, Jonas aut Wiszniewski, Wojciech aut Penney, Samantha aut Liu, Pengfei aut Bi, Weimin aut Lalani, Seema R. aut Schaaf, Christian P. aut Wangler, Michael F. aut Bacino, Carlos A. aut Lewis, Richard Alan aut Potocki, Lorraine aut Graham, Brett H. aut Belmont, John W. aut Scaglia, Fernando aut Orange, Jordan S. aut Jhangiani, Shalini N. aut Chiang, Theodore aut Doddapaneni, Harsha aut Hu, Jianhong aut Muzny, Donna M. aut Xia, Fan aut Beaudet, Arthur L. aut Boerwinkle, Eric aut Eng, Christine M. aut Plon, Sharon E. aut Sutton, V. Reid aut Gibbs, Richard A. aut Posey, Jennifer E. aut Yang, Yaping aut Lupski, James R. aut Enthalten in Genome medicine London : BioMed Central, 2009 9(2017), 1 vom: 21. März (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:9 year:2017 number:1 day:21 month:03 https://dx.doi.org/10.1186/s13073-017-0412-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2017 1 21 03 |
allfieldsGer |
10.1186/s13073-017-0412-6 doi (DE-627)SPR030652642 (SPR)s13073-017-0412-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut Lessons learned from additional research analyses of unsolved clinical exome cases 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2017 Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. Copy Number Variant (dpeaa)DE-He213 Molecular Diagnosis (dpeaa)DE-He213 Pathogenic Variant (dpeaa)DE-He213 Single Nucleotide Variant (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Coban-Akdemir, Zeynep aut Harel, Tamar aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Stray-Pedersen, Asbjørg aut Küry, Sébastien aut Mercier, Sandra aut Lessel, Davor aut Denecke, Jonas aut Wiszniewski, Wojciech aut Penney, Samantha aut Liu, Pengfei aut Bi, Weimin aut Lalani, Seema R. aut Schaaf, Christian P. aut Wangler, Michael F. aut Bacino, Carlos A. aut Lewis, Richard Alan aut Potocki, Lorraine aut Graham, Brett H. aut Belmont, John W. aut Scaglia, Fernando aut Orange, Jordan S. aut Jhangiani, Shalini N. aut Chiang, Theodore aut Doddapaneni, Harsha aut Hu, Jianhong aut Muzny, Donna M. aut Xia, Fan aut Beaudet, Arthur L. aut Boerwinkle, Eric aut Eng, Christine M. aut Plon, Sharon E. aut Sutton, V. Reid aut Gibbs, Richard A. aut Posey, Jennifer E. aut Yang, Yaping aut Lupski, James R. aut Enthalten in Genome medicine London : BioMed Central, 2009 9(2017), 1 vom: 21. März (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:9 year:2017 number:1 day:21 month:03 https://dx.doi.org/10.1186/s13073-017-0412-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2017 1 21 03 |
allfieldsSound |
10.1186/s13073-017-0412-6 doi (DE-627)SPR030652642 (SPR)s13073-017-0412-6-e DE-627 ger DE-627 rakwb eng Eldomery, Mohammad K. verfasserin aut Lessons learned from additional research analyses of unsolved clinical exome cases 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2017 Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. Copy Number Variant (dpeaa)DE-He213 Molecular Diagnosis (dpeaa)DE-He213 Pathogenic Variant (dpeaa)DE-He213 Single Nucleotide Variant (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 Coban-Akdemir, Zeynep aut Harel, Tamar aut Rosenfeld, Jill A. aut Gambin, Tomasz aut Stray-Pedersen, Asbjørg aut Küry, Sébastien aut Mercier, Sandra aut Lessel, Davor aut Denecke, Jonas aut Wiszniewski, Wojciech aut Penney, Samantha aut Liu, Pengfei aut Bi, Weimin aut Lalani, Seema R. aut Schaaf, Christian P. aut Wangler, Michael F. aut Bacino, Carlos A. aut Lewis, Richard Alan aut Potocki, Lorraine aut Graham, Brett H. aut Belmont, John W. aut Scaglia, Fernando aut Orange, Jordan S. aut Jhangiani, Shalini N. aut Chiang, Theodore aut Doddapaneni, Harsha aut Hu, Jianhong aut Muzny, Donna M. aut Xia, Fan aut Beaudet, Arthur L. aut Boerwinkle, Eric aut Eng, Christine M. aut Plon, Sharon E. aut Sutton, V. Reid aut Gibbs, Richard A. aut Posey, Jennifer E. aut Yang, Yaping aut Lupski, James R. aut Enthalten in Genome medicine London : BioMed Central, 2009 9(2017), 1 vom: 21. März (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:9 year:2017 number:1 day:21 month:03 https://dx.doi.org/10.1186/s13073-017-0412-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2017 1 21 03 |
language |
English |
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Enthalten in Genome medicine 9(2017), 1 vom: 21. März volume:9 year:2017 number:1 day:21 month:03 |
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Enthalten in Genome medicine 9(2017), 1 vom: 21. März volume:9 year:2017 number:1 day:21 month:03 |
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topic_facet |
Copy Number Variant Molecular Diagnosis Pathogenic Variant Single Nucleotide Variant Whole Exome Sequencing |
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Genome medicine |
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Eldomery, Mohammad K. @@aut@@ Coban-Akdemir, Zeynep @@aut@@ Harel, Tamar @@aut@@ Rosenfeld, Jill A. @@aut@@ Gambin, Tomasz @@aut@@ Stray-Pedersen, Asbjørg @@aut@@ Küry, Sébastien @@aut@@ Mercier, Sandra @@aut@@ Lessel, Davor @@aut@@ Denecke, Jonas @@aut@@ Wiszniewski, Wojciech @@aut@@ Penney, Samantha @@aut@@ Liu, Pengfei @@aut@@ Bi, Weimin @@aut@@ Lalani, Seema R. @@aut@@ Schaaf, Christian P. @@aut@@ Wangler, Michael F. @@aut@@ Bacino, Carlos A. @@aut@@ Lewis, Richard Alan @@aut@@ Potocki, Lorraine @@aut@@ Graham, Brett H. @@aut@@ Belmont, John W. @@aut@@ Scaglia, Fernando @@aut@@ Orange, Jordan S. @@aut@@ Jhangiani, Shalini N. @@aut@@ Chiang, Theodore @@aut@@ Doddapaneni, Harsha @@aut@@ Hu, Jianhong @@aut@@ Muzny, Donna M. @@aut@@ Xia, Fan @@aut@@ Beaudet, Arthur L. @@aut@@ Boerwinkle, Eric @@aut@@ Eng, Christine M. @@aut@@ Plon, Sharon E. @@aut@@ Sutton, V. Reid @@aut@@ Gibbs, Richard A. @@aut@@ Posey, Jennifer E. @@aut@@ Yang, Yaping @@aut@@ Lupski, James R. @@aut@@ |
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2017-03-21T00:00:00Z |
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594424275 |
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englisch |
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Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. 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Eldomery, Mohammad K. misc Copy Number Variant misc Molecular Diagnosis misc Pathogenic Variant misc Single Nucleotide Variant misc Whole Exome Sequencing Lessons learned from additional research analyses of unsolved clinical exome cases |
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Lessons learned from additional research analyses of unsolved clinical exome cases Copy Number Variant (dpeaa)DE-He213 Molecular Diagnosis (dpeaa)DE-He213 Pathogenic Variant (dpeaa)DE-He213 Single Nucleotide Variant (dpeaa)DE-He213 Whole Exome Sequencing (dpeaa)DE-He213 |
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Eldomery, Mohammad K. Coban-Akdemir, Zeynep Harel, Tamar Rosenfeld, Jill A. Gambin, Tomasz Stray-Pedersen, Asbjørg Küry, Sébastien Mercier, Sandra Lessel, Davor Denecke, Jonas Wiszniewski, Wojciech Penney, Samantha Liu, Pengfei Bi, Weimin Lalani, Seema R. Schaaf, Christian P. Wangler, Michael F. Bacino, Carlos A. Lewis, Richard Alan Potocki, Lorraine Graham, Brett H. Belmont, John W. Scaglia, Fernando Orange, Jordan S. Jhangiani, Shalini N. Chiang, Theodore Doddapaneni, Harsha Hu, Jianhong Muzny, Donna M. Xia, Fan Beaudet, Arthur L. Boerwinkle, Eric Eng, Christine M. Plon, Sharon E. Sutton, V. Reid Gibbs, Richard A. Posey, Jennifer E. Yang, Yaping Lupski, James R. |
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lessons learned from additional research analyses of unsolved clinical exome cases |
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Lessons learned from additional research analyses of unsolved clinical exome cases |
abstract |
Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. © The Author(s). 2017 |
abstractGer |
Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. © The Author(s). 2017 |
abstract_unstemmed |
Background Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. Methods We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. Results Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts. © The Author(s). 2017 |
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Coban-Akdemir, Zeynep Harel, Tamar Rosenfeld, Jill A. Gambin, Tomasz Stray-Pedersen, Asbjørg Küry, Sébastien Mercier, Sandra Lessel, Davor Denecke, Jonas Wiszniewski, Wojciech Penney, Samantha Liu, Pengfei Bi, Weimin Lalani, Seema R. Schaaf, Christian P. Wangler, Michael F. Bacino, Carlos A. Lewis, Richard Alan Potocki, Lorraine Graham, Brett H. Belmont, John W. Scaglia, Fernando Orange, Jordan S. Jhangiani, Shalini N. Chiang, Theodore Doddapaneni, Harsha Hu, Jianhong Muzny, Donna M. Xia, Fan Beaudet, Arthur L. Boerwinkle, Eric Eng, Christine M. Plon, Sharon E. Sutton, V. Reid Gibbs, Richard A. Posey, Jennifer E. Yang, Yaping Lupski, James R. |
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Coban-Akdemir, Zeynep Harel, Tamar Rosenfeld, Jill A. Gambin, Tomasz Stray-Pedersen, Asbjørg Küry, Sébastien Mercier, Sandra Lessel, Davor Denecke, Jonas Wiszniewski, Wojciech Penney, Samantha Liu, Pengfei Bi, Weimin Lalani, Seema R. Schaaf, Christian P. Wangler, Michael F. Bacino, Carlos A. Lewis, Richard Alan Potocki, Lorraine Graham, Brett H. Belmont, John W. Scaglia, Fernando Orange, Jordan S. Jhangiani, Shalini N. Chiang, Theodore Doddapaneni, Harsha Hu, Jianhong Muzny, Donna M. Xia, Fan Beaudet, Arthur L. Boerwinkle, Eric Eng, Christine M. Plon, Sharon E. Sutton, V. Reid Gibbs, Richard A. Posey, Jennifer E. Yang, Yaping Lupski, James R. |
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If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). Conclusion An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. 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score |
7.400629 |