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

TL;DR

This paper reviews current and emerging diagnostic testing methods for Mendelian conditions beyond exome sequencing, discussing their limitations, potential, and guiding clinicians on next steps after inconclusive results.

Contribution

It provides a comprehensive framework and guidance for clinicians on navigating advanced genetic testing options and next steps after negative or inconclusive initial evaluations.

Findings

Limitations of exome sequencing in diagnosing Mendelian conditions.

Emerging technologies like long-read sequencing offer new diagnostic possibilities.

Guidance on when to refer to specialized consortia like GREGoR.

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 or RNA 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 a consortium such as GREGoR, which is focused on elucidating the underlying cause of rare unsolved genetic disorders.