Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study

Abstract

BackgroundExome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology.MethodsPatients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing.ResultsOverall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results.ConclusionsThis study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.

Diagnostic yield of clinical exome sequencing in adulthood in medical genetics clinics

“…Fourteen variants of unknown significance in There are a small number of studies using ES (research or clinical) in adults which are summarized in Table S5. The diagnostic yield ranged from 17% to 60% with a wide range of phenotypes in those studies (da Graça et al, 2022;Guo et al, 2021;Minardi et al, 2020;Mu et al, 2019;Posey et al, 2016;Sabo et al, 2020;Shickh et al, 2021).…”

Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA)

“…This discordance can be most likely attributed to the age difference of the patient cohorts since other initiatives focus on pediatric cases often presenting with severe neurodevelopmental phenotypes and/or congenital malformations [ 14 , 18 ]. The a priori chance of identifying an underlying molecular cause is higher in children, presenting with more severe and typical phenotypes, as opposed to adults which often present with an atypical or attenuated phenotype [ 9 , 34 ]. Nevertheless, with a diagnostic rate of 18% we show that advanced age should not be a counter-argument to initiate exome-based genetic testing.…”

Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency

“…Therefore, they may represent extremes of the PPAP phenotypic spectrum, possibly caused by genetic or environmental modifiers. Another patient carrying a POLE p.(Tyr458Asn) variant was diagnosed with a colorectal cancer aged 25 years and has an affected daughter diagnosed with multiple colorectal adenomas at age 17 years (Shickh et al, 2021). Despite not raising suspicion for CMMRD according to C4CMMRD criteria, these are very early‐onset phenotypes.…”