Beyond the Exome: What’s Next in Diagnostic Testing for Mendelian Conditions

Authors

Monica H Wojcik
Chloe M Reuter
Shruti Marwaha
Medhat Mahmoud
Michael H Duyzend
Hayk Barseghyan
Bo Yuan
Philip M Boone
Emily E Groopman
Emmanuèle C Délot
Deepti Jain
Alba Sanchis-Juan
Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium
Lea M Starita
Michael Talkowski
Stephen B Montgomery
Michael J Bamshad
Jessica X Chong
Matthew T Wheeler
Seth I Berger
Anne O'Donnell-Luria
Fritz J Sedlazeck
Danny E Miller

Publication Date

8-3-2023

Journal

American Journal of Human Genetics

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

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

Comments

PMID: 37541186