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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Eldomery, Mohammad K. [verfasserIn] 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.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	Copy Number Variant Molecular Diagnosis Pathogenic Variant Single Nucleotide Variant Whole Exome Sequencing

Anmerkung:	© The Author(s). 2017

Übergeordnetes Werk:	Enthalten in: Genome medicine - London : BioMed Central, 2009, 9(2017), 1 vom: 21. März
Übergeordnetes Werk:	volume:9 ; year:2017 ; number:1 ; day:21 ; month:03

Links:	Volltext

DOI / URN:	10.1186/s13073-017-0412-6

Katalog-ID:	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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700	1		\|a Stray-Pedersen, Asbjørg \|4 aut
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700	1		\|a Denecke, Jonas \|4 aut
700	1		\|a Wiszniewski, Wojciech \|4 aut
700	1		\|a Penney, Samantha \|4 aut
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700	1		\|a Bacino, Carlos A. \|4 aut
700	1		\|a Lewis, Richard Alan \|4 aut
700	1		\|a Potocki, Lorraine \|4 aut
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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
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700	1		\|a Lupski, James R. \|4 aut
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allfields	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
source	Enthalten in Genome medicine 9(2017), 1 vom: 21. März volume:9 year:2017 number:1 day:21 month:03
sourceStr	Enthalten in Genome medicine 9(2017), 1 vom: 21. März volume:9 year:2017 number:1 day:21 month:03
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Copy Number Variant Molecular Diagnosis Pathogenic Variant Single Nucleotide Variant Whole Exome Sequencing
isfreeaccess_bool	true
container_title	Genome medicine
authorswithroles_txt_mv	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@@
publishDateDaySort_date	2017-03-21T00:00:00Z
hierarchy_top_id	594424275
id	SPR030652642
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR030652642</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520010405.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2017 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-017-0412-6</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR030652642</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s13073-017-0412-6-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Eldomery, Mohammad K.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Lessons learned from additional research analyses of unsolved clinical exome cases</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s). 2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="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. 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author	Eldomery, Mohammad K.
spellingShingle	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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topic_title	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
topic	misc Copy Number Variant misc Molecular Diagnosis misc Pathogenic Variant misc Single Nucleotide Variant misc Whole Exome Sequencing
topic_unstemmed	misc Copy Number Variant misc Molecular Diagnosis misc Pathogenic Variant misc Single Nucleotide Variant misc Whole Exome Sequencing
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title	Lessons learned from additional research analyses of unsolved clinical exome cases
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title_full	Lessons learned from additional research analyses of unsolved clinical exome cases
author_sort	Eldomery, Mohammad K.
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author_browse	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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title_sort	lessons learned from additional research analyses of unsolved clinical exome cases
title_auth	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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title_short	Lessons learned from additional research analyses of unsolved clinical exome cases
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up_date	2024-07-03T19:21:04.375Z
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR030652642</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520010405.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2017 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-017-0412-6</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR030652642</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s13073-017-0412-6-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Eldomery, Mohammad K.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Lessons learned from additional research analyses of unsolved clinical exome cases</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s). 2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="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. 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Lessons learned from additional research analyses of unsolved clinical exome cases

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