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

Monica H. Wojcik, 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.
Chloe M. Reuter, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Shruti Marwaha, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Medhat Mahmoud, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Michael H. Duyzend, 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.
Hayk Barseghyan, 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.
Bo Yuan, Department of Molecular and Human Genetics and Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Philip M. Boone, 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.
Emily E. Groopman, 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.
Emmanuèle C. Délot, 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.
Deepti Jain, Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA 98195, USA.
Alba Sanchis-Juan, 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.

Document Type

Journal Article

Publication Date

8-3-2023

Journal

American journal of human genetics

Volume

110

Issue

8

DOI

10.1016/j.ajhg.2023.06.009

Keywords

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

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.

Department

Genomics and Precision Medicine

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