A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

doi:10.1038/s41436-018-0044-2

. 2019 Jan;21(1):161-172.

doi: 10.1038/s41436-018-0044-2. Epub 2018 Jun 15.

A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

Collaborators, Affiliations

Collaborators

Undiagnosed Diseases Network:
David R Adams, Mercedes E Alejandro, Patrick Allard, Euan A Ashley, Mahshid S Azamian, Carlos A Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F Batzli, Alan H Beggs, Babak Behnam, Hugo J Bellen, Jonathan A Bernstein, Anna Bican, David P Bick, Camille L Birch, Devon Bonner, Braden E Boone, Bret L Bostwick, Lauren C Briere, Donna M Brown, Matthew Brush, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Shan Chen, Gary D Clark, Terra R Coakley, Joy D Cogan, Cynthia M Cooper, Heidi Cope, William J Craigen, Precilla D'Souza, Mariska Davids, Jean M Davidson, Jyoti G Dayal, Esteban C Dell'Angelica, Shweta U Dhar, Katrina M Dipple, Laurel A Donnell-Fink, Naghmeh Dorrani, Daniel C Dorset, Emilie D Douine, David D Draper, Annika M Dries, David J Eckstein, Lisa T Emrick, Christine M Eng, Gregory M Enns, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Paul G Fisher, Brent L Fogel, Noah D Friedman, William A Gahl, Emily Glanton, Rena A Godfrey, David B Goldstein, Sarah E Gould, Jean-Philippe F Gourdine, Catherine A Groden, Andrea L Gropman, Melissa Haendel, Rizwan Hamid, Neil A Hanchard, Lori H Handley, Matthew R Herzog, Ingrid A Holm, Jason Hom, Ellen M Howerton, Yong Huang, Howard J Jacob, Mahim Jain, Yong-Hui Jiang, Jean M Johnston, Angela L Jones, David M Koeller, Isaac S Kohane, Jennefer N Kohler, Donna M Krasnewich, Elizabeth L Krieg, Joel B Krier, Jennifer E Kyle, Seema R Lalani, C Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H Lee, Hane Lee, Shawn E Levy, Richard A Lewis, Sharyn A Lincoln, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, Marta M Majcherska, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Thomas C Markello, Ronit Marom, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E McCormack, Alexa T McCray, Jason D Merker, Thomas O Metz, Matthew Might, Paolo M Moretti, Marie Morimoto, John J Mulvihill, Jennifer L Murphy, Donna M Muzny, Michele E Nehrebecky, Stan F Nelson, J Scott Newberry, John H Newman, Sarah K Nicholas, Donna Novacic, Jordan S Orange, J Carl Pallais, Christina Gs Palmer, Jeanette C Papp, Neil H Parker, Loren Dm Pena, John A Phillips 3rd, Jennifer E Posey, John H Postlethwait, Lorraine Potocki, Barbara N Pusey, Chloe M Reuter, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Jacinda B Sampson, Susan L Samson, Kelly Schoch, Molly C Schroeder, Daryl A Scott, Prashant Sharma, Vandana Shashi, Edwin K Silverman, Janet S Sinsheimer, Kevin S Smith, Rebecca C Spillmann, Joan M Stoler, Nicholas Stong, Jennifer A Sullivan, David A Sweetser, Queenie K-G Tan, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Tiina K Urv, Zaheer M Valivullah, Eric Vilain, Tiphanie P Vogel, Daryl M Waggott, Colleen E Wahl, Nicole M Walley, Chris A Walsh, Jijun Wan, Michael F Wangler, Patricia A Ward, Katrina M Waters, Bobbie-Jo M Webb-Robertson, Monte Westerfield, Matthew T Wheeler, Anastasia L Wise, Lynne A Wolfe, Elizabeth A Worthey, Shinya Yamamoto, Yaping Yang, Amanda J Yoon, Guoyun Yu, Diane B Zastrow, Chunli Zhao, Allison Zheng

Affiliations

¹ Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA. vandana.shashi@duke.edu.
² Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA.
³ Institute for Genomic Medicine, Columbia University, New York, New York, USA.
⁴ Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.

PMID: 29907797
PMCID: PMC6295275
DOI: 10.1038/s41436-018-0044-2

A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

Vandana Shashi et al. Genet Med. 2019 Jan.

. 2019 Jan;21(1):161-172.

doi: 10.1038/s41436-018-0044-2. Epub 2018 Jun 15.

Collaborators

Undiagnosed Diseases Network:
David R Adams, Mercedes E Alejandro, Patrick Allard, Euan A Ashley, Mahshid S Azamian, Carlos A Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F Batzli, Alan H Beggs, Babak Behnam, Hugo J Bellen, Jonathan A Bernstein, Anna Bican, David P Bick, Camille L Birch, Devon Bonner, Braden E Boone, Bret L Bostwick, Lauren C Briere, Donna M Brown, Matthew Brush, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Shan Chen, Gary D Clark, Terra R Coakley, Joy D Cogan, Cynthia M Cooper, Heidi Cope, William J Craigen, Precilla D'Souza, Mariska Davids, Jean M Davidson, Jyoti G Dayal, Esteban C Dell'Angelica, Shweta U Dhar, Katrina M Dipple, Laurel A Donnell-Fink, Naghmeh Dorrani, Daniel C Dorset, Emilie D Douine, David D Draper, Annika M Dries, David J Eckstein, Lisa T Emrick, Christine M Eng, Gregory M Enns, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Paul G Fisher, Brent L Fogel, Noah D Friedman, William A Gahl, Emily Glanton, Rena A Godfrey, David B Goldstein, Sarah E Gould, Jean-Philippe F Gourdine, Catherine A Groden, Andrea L Gropman, Melissa Haendel, Rizwan Hamid, Neil A Hanchard, Lori H Handley, Matthew R Herzog, Ingrid A Holm, Jason Hom, Ellen M Howerton, Yong Huang, Howard J Jacob, Mahim Jain, Yong-Hui Jiang, Jean M Johnston, Angela L Jones, David M Koeller, Isaac S Kohane, Jennefer N Kohler, Donna M Krasnewich, Elizabeth L Krieg, Joel B Krier, Jennifer E Kyle, Seema R Lalani, C Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H Lee, Hane Lee, Shawn E Levy, Richard A Lewis, Sharyn A Lincoln, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, Marta M Majcherska, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Thomas C Markello, Ronit Marom, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E McCormack, Alexa T McCray, Jason D Merker, Thomas O Metz, Matthew Might, Paolo M Moretti, Marie Morimoto, John J Mulvihill, Jennifer L Murphy, Donna M Muzny, Michele E Nehrebecky, Stan F Nelson, J Scott Newberry, John H Newman, Sarah K Nicholas, Donna Novacic, Jordan S Orange, J Carl Pallais, Christina Gs Palmer, Jeanette C Papp, Neil H Parker, Loren Dm Pena, John A Phillips 3rd, Jennifer E Posey, John H Postlethwait, Lorraine Potocki, Barbara N Pusey, Chloe M Reuter, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Jacinda B Sampson, Susan L Samson, Kelly Schoch, Molly C Schroeder, Daryl A Scott, Prashant Sharma, Vandana Shashi, Edwin K Silverman, Janet S Sinsheimer, Kevin S Smith, Rebecca C Spillmann, Joan M Stoler, Nicholas Stong, Jennifer A Sullivan, David A Sweetser, Queenie K-G Tan, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Tiina K Urv, Zaheer M Valivullah, Eric Vilain, Tiphanie P Vogel, Daryl M Waggott, Colleen E Wahl, Nicole M Walley, Chris A Walsh, Jijun Wan, Michael F Wangler, Patricia A Ward, Katrina M Waters, Bobbie-Jo M Webb-Robertson, Monte Westerfield, Matthew T Wheeler, Anastasia L Wise, Lynne A Wolfe, Elizabeth A Worthey, Shinya Yamamoto, Yaping Yang, Amanda J Yoon, Guoyun Yu, Diane B Zastrow, Chunli Zhao, Allison Zheng

Affiliations

¹ Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA. vandana.shashi@duke.edu.
² Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA.
³ Institute for Genomic Medicine, Columbia University, New York, New York, USA.
⁴ Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.

PMID: 29907797
PMCID: PMC6295275
DOI: 10.1038/s41436-018-0044-2

Abstract

Purpose: Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals.

Methods: In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred.

Results: Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%).

Conclusions: Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.

Keywords: Exome sequencing; Genome sequencing; Phenotyping; Rare diseases; Undiagnosed diseases.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

David Goldstein is a founder of and holds equity in Pairnomix and Praxis, serves as a consultant to AstraZeneca, and has research supported by Janssen, Gilead, Biogen, AstraZeneca, and UCB.

The rest of the authors declare no conflicts of interest related to this manuscript.

Figures

**Figure 1**
Flowchart illustrating the approach to the ES negatives and the resolution with the different modalities

See this image and copyright information in PMC

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References

1. Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880–1887. - PMC - PubMed
1. Gilissen C, Hoischen A, Brunner HG, Veltman JA. Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011;12(9):228. - PMC - PubMed
1. Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353–361. - PMC - PubMed
1. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–1879. - PMC - PubMed
1. Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19(2):209–214. - PubMed

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[1] Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880–1887. - PMC - PubMed

[2] Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880–1887. - PMC - PubMed

[3] Gilissen C, Hoischen A, Brunner HG, Veltman JA. Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011;12(9):228. - PMC - PubMed

[4] Gilissen C, Hoischen A, Brunner HG, Veltman JA. Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011;12(9):228. - PMC - PubMed

[5] Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353–361. - PMC - PubMed

[6] Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353–361. - PMC - PubMed

[7] Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–1879. - PMC - PubMed

[8] Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–1879. - PMC - PubMed

[9] Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19(2):209–214. - PubMed

[10] Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19(2):209–214. - PubMed

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A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

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A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

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