Title | Beyond the exome: what's next in diagnostic testing for Mendelian conditions. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | 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, Starita, LM, Talkowski, M, Montgomery, SB, Bamshad, MJ, Chong, JX, Wheeler, MT, Berger, SI, O'Donnell-Luria, A, Sedlazeck, FJ, Miller, DE |
Corporate Authors | Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium |
Journal | ArXiv |
Date Published | 2023 Jan 18 |
ISSN | 2331-8422 |
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. |
DOI | 10.1002/ajmg.a.63053 |
Alternate Journal | ArXiv |
PubMed ID | 36713248 |
PubMed Central ID | PMC9882576 |
Grant List | U24 HG011746 / HG / NHGRI NIH HHS / United States U01 HG011745 / HG / NHGRI NIH HHS / United States U01 HG011762 / HG / NHGRI NIH HHS / United States U01 HG011744 / HG / NHGRI NIH HHS / United States DP5 OD033357 / OD / NIH HHS / United States U01 HG011758 / HG / NHGRI NIH HHS / United States K23 HD102589 / HD / NICHD NIH HHS / United States U01 HG011755 / HG / NHGRI NIH HHS / United States |