Review

. 2023 Aug 3;110(8):1229-1248.

doi: 10.1016/j.ajhg.2023.06.009.

Beyond the exome: What's next in diagnostic testing for Mendelian conditions

Monica H Wojcik¹, Chloe M Reuter², Shruti Marwaha², Medhat Mahmoud³, Michael H Duyzend⁴, Hayk Barseghyan⁵, Bo Yuan⁶, Philip M Boone⁴, Emily E Groopman⁴, Emmanuèle C Délot⁷, Deepti Jain⁸, Alba Sanchis-Juan⁹; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium; Lea M Starita¹⁰, Michael Talkowski¹¹, Stephen B Montgomery¹², Michael J Bamshad¹³, Jessica X Chong¹⁴, Matthew T Wheeler², Seth I Berger¹⁵, Anne O'Donnell-Luria⁴, Fritz J Sedlazeck¹⁶, Danny E Miller¹⁷

Collaborators, Affiliations

Collaborators

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium:
Siwaar Abouhala, Jessica Albert, Miguel Almalvez, Raquel Alvarez, Mutaz Amin, Peter Anderson, Swaroop Aradhya, Euan Ashley, Themistocles Assimes, Light Auriga, Christina Austin-Tse, Mike Bamshad, Hayk Barseghyan, Samantha Baxter, Sairam Behera, Shaghayegh Beheshti, Gill Bejerano, Seth Berger, Jon Bernstein, Sabrina Best, Benjamin Blankenmeister, Elizabeth Blue, Eric Boerwinkle, Emily Bonkowski, Devon Bonner, Philip Boone, Miriam Bornhorst, Tugce Bozkurt-Yozgatli, Harrison Brand, Kati Buckingham, Daniel Calame, Silvia Casadei, Lisa Chadwick, Clarisa Chavez, Ziwei Chen, Ivan Chinn, Jessica Chong, Zeynep Coban-Akdemir, Andrea J Cohen, Sarah Conner, Matthew Conomos, Karen Coveler, Ya Allen Cui, Sara Currin, Robert Daber, Zain Dardas, Colleen Davis, Moez Dawood, Ivan de Dios, Celine de Esch, Meghan Delaney, Emmanuèle Délot, Stephanie DiTroia, Harsha Doddapaneni, Haowei Du, Ruizhi Duan, Shannon Dugan-Perez, Nhat Duong, Michael Duyzend, Evan Eichler, Sara Emami, Jawid Fatih, Jamie Fraser, Vincent Fusaro, Miranda Galey, Vijay Ganesh, Kiran Garimella, Richard Gibbs, Casey Gifford, Amy Ginsburg, Pagé Goddard, Stephanie Gogarten, Nikhita Gogate, William Gordon, John E Gorzynski, William Greenleaf, Christopher Grochowski, Emily Groopman, Rodrigo Guarischi Sousa, Sanna Gudmundsson, Ashima Gulati, Daniel Guo, Walker Hale, Stacey Hall, William Harvey, Megan Hawley, Ben Heavner, Isabella Herman, Martha Horike-Pyne, Jianhong Hu, Yongqing Huang, James Hwang, Gail Jarvik, Tanner Jensen, Shalini Jhangiani, David Jimenez-Morales, Christopher Jin, Ahmed K Saad, Amanda Kahn-Kirby, Jessica Kain, Parneet Kaur, Laura Keehan, Susan Knoblach, Arthur Ko, Jennefer Kohler, Anshul Kundaje, Soumya Kundu, Samuel M Lancaster, Katie Larsson, Gabrielle Lemire, Richard Lewis, Wei Li, Yidan Li, Pengfei Liu, Jonathan LoTempio, James Lupski, Jialan Ma, Daniel MacArthur, Medhat Mahmoud, Nirav Malani, Brian Mangilog, Dana Marafi, Sofia Marmolejos, Daniel Marten, Eva Martinez, Colby Marvin, Shruti Marwaha, Francesco Kumara Mastrorosa, Dena Matalon, Susanne May, Sean McGee, Lauren Meador, Heather Mefford, Hector Rodrigo Mendez, Alexander Miller, Danny E Miller, Tadahiro Mitani, Stephen Montgomery, Hala Mohamed Moussa, Mariana Moyses, Chloe Munderloh, Donna Muzny, Sarah Nelson, Matthew B Neu, Jonathan Nguyen, Thuy-Mi P Nguyen, Robert Nussbaum, Keith Nykamp, William O'Callaghan, Emily O'Heir, Melanie O'Leary, Jeren Olsen, Ikeoluwa Osei-Owusu, Anne O'Donnell-Luria, Evin Padhi, Lynn Pais, Miao Pan, Piyush Panchal, Karynne Patterson, Sheryl Payne, Davut Pehlivan, Paul Petrowski, Alicia Pham, Georgia Pitsava, Astaria Podesta, Sarah Ponce, Jennifer Posey, Jaime Prosser, Thomas Quertermous, Archana Rai, Arun Ramani, Heidi Rehm, Chloe Reuter, Jason Reuter, Matthew Richardson, Andres Rivera-Munoz, Oriane Rubio, Aniko Sabo, Monica Salani, Kaitlin Samocha, Alba Sanchis-Juan, Sarah Savage, Stuart Scott, Evette Scott, Fritz Sedlazeck, Gulalai Shah, Ali Shojaie, Mugdha Singh, Josh Smith, Kevin Smith, Hana Snow, Michael Snyder, Kayla Socarras, Lea Starita, Brigitte Stark, Sarah Stenton, Andrew Stergachis, Adrienne Stilp, Laksshman Sundaram, V Reid Sutton, Jui-Cheng Tai, Michael Talkowski, Christina Tise, Catherine Tong, Philip Tsao, Rachel Ungar, Grace VanNoy, Eric Vilain, Isabella Voutos, Kim Walker, Ben Weisburd, Jeff Weiss, Chris Wellington, Ziming Weng, Emily Westheimer, Marsha Wheeler, Matthew Wheeler, Laurens Wiel, Michael Wilson, Monica Wojcik, Quenna Wong, Issac Wong, Changrui Xiao, Rachita Yadav, Qian Yi, Bo Yuan, Jianhua Zhao, Jimmy Zhen, Harry Zhou

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Center for Genetics Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
⁶ Department of Molecular and Human Genetics and Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁷ Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA; Center for Genetics Medicine Research, Children's National Research and Innovation Campus, Washington, DC, USA; Department of Pediatrics, George Washington University, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
⁸ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA 98195, USA.
⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
¹¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁴ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁵ Center for Genetics Medicine Research and Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA.
¹⁶ Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Computer Science, Rice University, 6100 Main Street, Houston, TX 77005, USA.
¹⁷ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: dm1@uw.edu.

PMID: 37541186
PMCID: PMC10432150
DOI: 10.1016/j.ajhg.2023.06.009

Review

Beyond the exome: What's next in diagnostic testing for Mendelian conditions

Monica H Wojcik et al. Am J Hum Genet. 2023.

. 2023 Aug 3;110(8):1229-1248.

doi: 10.1016/j.ajhg.2023.06.009.

Authors

Collaborators

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium:
Siwaar Abouhala, Jessica Albert, Miguel Almalvez, Raquel Alvarez, Mutaz Amin, Peter Anderson, Swaroop Aradhya, Euan Ashley, Themistocles Assimes, Light Auriga, Christina Austin-Tse, Mike Bamshad, Hayk Barseghyan, Samantha Baxter, Sairam Behera, Shaghayegh Beheshti, Gill Bejerano, Seth Berger, Jon Bernstein, Sabrina Best, Benjamin Blankenmeister, Elizabeth Blue, Eric Boerwinkle, Emily Bonkowski, Devon Bonner, Philip Boone, Miriam Bornhorst, Tugce Bozkurt-Yozgatli, Harrison Brand, Kati Buckingham, Daniel Calame, Silvia Casadei, Lisa Chadwick, Clarisa Chavez, Ziwei Chen, Ivan Chinn, Jessica Chong, Zeynep Coban-Akdemir, Andrea J Cohen, Sarah Conner, Matthew Conomos, Karen Coveler, Ya Allen Cui, Sara Currin, Robert Daber, Zain Dardas, Colleen Davis, Moez Dawood, Ivan de Dios, Celine de Esch, Meghan Delaney, Emmanuèle Délot, Stephanie DiTroia, Harsha Doddapaneni, Haowei Du, Ruizhi Duan, Shannon Dugan-Perez, Nhat Duong, Michael Duyzend, Evan Eichler, Sara Emami, Jawid Fatih, Jamie Fraser, Vincent Fusaro, Miranda Galey, Vijay Ganesh, Kiran Garimella, Richard Gibbs, Casey Gifford, Amy Ginsburg, Pagé Goddard, Stephanie Gogarten, Nikhita Gogate, William Gordon, John E Gorzynski, William Greenleaf, Christopher Grochowski, Emily Groopman, Rodrigo Guarischi Sousa, Sanna Gudmundsson, Ashima Gulati, Daniel Guo, Walker Hale, Stacey Hall, William Harvey, Megan Hawley, Ben Heavner, Isabella Herman, Martha Horike-Pyne, Jianhong Hu, Yongqing Huang, James Hwang, Gail Jarvik, Tanner Jensen, Shalini Jhangiani, David Jimenez-Morales, Christopher Jin, Ahmed K Saad, Amanda Kahn-Kirby, Jessica Kain, Parneet Kaur, Laura Keehan, Susan Knoblach, Arthur Ko, Jennefer Kohler, Anshul Kundaje, Soumya Kundu, Samuel M Lancaster, Katie Larsson, Gabrielle Lemire, Richard Lewis, Wei Li, Yidan Li, Pengfei Liu, Jonathan LoTempio, James Lupski, Jialan Ma, Daniel MacArthur, Medhat Mahmoud, Nirav Malani, Brian Mangilog, Dana Marafi, Sofia Marmolejos, Daniel Marten, Eva Martinez, Colby Marvin, Shruti Marwaha, Francesco Kumara Mastrorosa, Dena Matalon, Susanne May, Sean McGee, Lauren Meador, Heather Mefford, Hector Rodrigo Mendez, Alexander Miller, Danny E Miller, Tadahiro Mitani, Stephen Montgomery, Hala Mohamed Moussa, Mariana Moyses, Chloe Munderloh, Donna Muzny, Sarah Nelson, Matthew B Neu, Jonathan Nguyen, Thuy-Mi P Nguyen, Robert Nussbaum, Keith Nykamp, William O'Callaghan, Emily O'Heir, Melanie O'Leary, Jeren Olsen, Ikeoluwa Osei-Owusu, Anne O'Donnell-Luria, Evin Padhi, Lynn Pais, Miao Pan, Piyush Panchal, Karynne Patterson, Sheryl Payne, Davut Pehlivan, Paul Petrowski, Alicia Pham, Georgia Pitsava, Astaria Podesta, Sarah Ponce, Jennifer Posey, Jaime Prosser, Thomas Quertermous, Archana Rai, Arun Ramani, Heidi Rehm, Chloe Reuter, Jason Reuter, Matthew Richardson, Andres Rivera-Munoz, Oriane Rubio, Aniko Sabo, Monica Salani, Kaitlin Samocha, Alba Sanchis-Juan, Sarah Savage, Stuart Scott, Evette Scott, Fritz Sedlazeck, Gulalai Shah, Ali Shojaie, Mugdha Singh, Josh Smith, Kevin Smith, Hana Snow, Michael Snyder, Kayla Socarras, Lea Starita, Brigitte Stark, Sarah Stenton, Andrew Stergachis, Adrienne Stilp, Laksshman Sundaram, V Reid Sutton, Jui-Cheng Tai, Michael Talkowski, Christina Tise, Catherine Tong, Philip Tsao, Rachel Ungar, Grace VanNoy, Eric Vilain, Isabella Voutos, Kim Walker, Ben Weisburd, Jeff Weiss, Chris Wellington, Ziming Weng, Emily Westheimer, Marsha Wheeler, Matthew Wheeler, Laurens Wiel, Michael Wilson, Monica Wojcik, Quenna Wong, Issac Wong, Changrui Xiao, Rachita Yadav, Qian Yi, Bo Yuan, Jianhua Zhao, Jimmy Zhen, Harry Zhou

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Center for Genetics Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
⁶ Department of Molecular and Human Genetics and Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁷ Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA; Center for Genetics Medicine Research, Children's National Research and Innovation Campus, Washington, DC, USA; Department of Pediatrics, George Washington University, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
⁸ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA 98195, USA.
⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
¹¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁴ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁵ Center for Genetics Medicine Research and Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA.
¹⁶ Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Computer Science, Rice University, 6100 Main Street, Houston, TX 77005, USA.
¹⁷ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: dm1@uw.edu.

PMID: 37541186
PMCID: PMC10432150
DOI: 10.1016/j.ajhg.2023.06.009

Abstract

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.

Keywords: PacBio sequencing; RNA sequencing; exome reanalysis; long-read sequencing; meatabolomics; nanopore sequencing; non-diagnostic exome; optical genome mapping.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests C.M.R. is a consultant for My Gene Counsel. H.B. is a shareholder of Bionano Genomics Inc, Pacific Biosciences Inc, and Illumina Inc. B.Y. has received royalties from UpToDate. A.O.-L. is on the SAB of Congenica. S.B.M. is a consultant for BioMarin, MyOme, and Tenaya Therapeutics. M.E.T. consults for BrigeBio Pharma and receives research funding and/or reagents from Illumina Inc., Levo Therapeutics, and Microsoft Inc. M.T.W. holds stock in Personalis, Inc. F.J.S. has received travel support to speak on behalf of ONT and PacBio. D.E.M. holds stock options in MyOme and is engaged in a research agreement with ONT, is on a scientific advisory board at ONT, and they have paid for him to travel to speak on their behalf.

Figures

**Figure 1**
Evaluation of individuals unsolved after ES Testing paths and options for individuals with clinical findings that cannot be partially or fully explained by a precise genetic diagnosis after exome sequencing are shown. In each path, exome reanalysis should be considered first. Many options are similar among the various paths but are of highest diagnostic yield at different steps of the evaluation process.

See this image and copyright information in PMC

Update of

Beyond the exome: what's next in diagnostic testing for Mendelian conditions.
Wojcik MH, Reuter CM, Marwaha S, Mahmoud M, Duyzend MH, Barseghyan H, Yuan B, Boone PM, Groopman EE, Délot EC, Jain D, Sanchis-Juan A; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium; Starita LM, Talkowski M, Montgomery SB, Bamshad MJ, Chong JX, Wheeler MT, Berger SI, O'Donnell-Luria A, Sedlazeck FJ, Miller DE. Wojcik MH, et al. ArXiv [Preprint]. 2023 Jan 18:arXiv:2301.07363v1. ArXiv. 2023. Update in: Am J Hum Genet. 2023 Aug 3;110(8):1229-1248. doi: 10.1016/j.ajhg.2023.06.009. PMID: 36713248 Free PMC article. Updated. Preprint.

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Beyond the exome: What's next in diagnostic testing for Mendelian conditions

Collaborators

Affiliations

Beyond the exome: What's next in diagnostic testing for Mendelian conditions

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases