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

TitleBeyond the exome: What's next in diagnostic testing for Mendelian conditions.
Publication TypeJournal Article
Year of Publication2023
AuthorsWojcik, 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 AuthorsGenomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium
JournalAm J Hum Genet
Date Published2023 Aug 03
KeywordsExome, Exome Sequencing, Genetic Testing, Humans, Phenotype, Rare Diseases, Sequence Analysis, DNA

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.

Alternate JournalAm J Hum Genet
PubMed ID37541186
PubMed Central IDPMC10432150
Grant ListU01 HG011758 / HG / NHGRI NIH HHS / United States
U01 HG011762 / HG / NHGRI NIH HHS / United States
U01 HG011755 / HG / NHGRI NIH HHS / United States
U01 HG011745 / HG / NHGRI NIH HHS / United States
U01 HG011744 / HG / NHGRI NIH HHS / United States
U24 HG011746 / HG / NHGRI NIH HHS / United States
DP5 OD033357 / OD / NIH HHS / United States
K23 HD102589 / HD / NICHD NIH HHS / United States

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