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

Mainali, Apurba; Athey, Taryn; Bahl, Shalini; Hung, Clara Hiu-Ling; Caluseriu, Oana; Chan, Alicia; Eaton, Alison; Ghai, Shailly Jain; Kannu, Peter; MacPherson, Melissa J; Niederhoffer, Karen Y.; Siriwardena, Komudi; Mercimek‐Andrews, Saadet

doi:10.1002/ajmg.a.63053

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…Similar diagnostic yields have been reported from neurogenetic clinics elsewhere, including 33% from a neurogenetics clinic in Israel, 21 27% in Argentina 22 and 30% in the United States 23 . However, lower diagnostic yields have been reported from other settings, including a diagnostic yield of 21% from exome sequencing for adolescents and adults with neurogenetic conditions in Australia, 6 19.5% from an adult general genetics clinic in Canada 24 and 17–19% from an unselected cohort referred to a medical genomics laboratory in the United States 25,26 . Although not directly comparable, the higher diagnostic rates observed in our and previous studies where MDT assessments took place prior to testing, compared with those reported by genomic laboratories, may reflect the additional benefit of an iterative MDT clinical assessment and/or multiple testing pathways.…”

Section: Discussionsupporting

confidence: 62%

Informing a value care model: lessons from an integrated adult neurogenomics clinic

McLean

Tchan

Devery

et al. 2023

Internal Medicine Journal

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BackgroundAdvances in genomics provide improved opportunities for diagnosis of complex neurogenetic disorders, yet the optimal approach to translate these benefits to the outpatient clinic is unclear.AimsWe retrospectively reviewed referral indications and outcomes of an integrated multidisciplinary team (MDT) clinic pathway for adults with suspected neurogenetic disorders. The associated cost implications were estimated.MethodsConsecutive patients who attended the neurogenomics clinic from January 2017 to April 2020 were included. The clinic comprised neurologists, clinical geneticists and genetic counsellors, who assessed each patient concurrently.ResultsNinety‐nine new patients were referred spanning 45 different clinical diagnoses. Following MDT clinical assessment, 23% (23/99) of referral diagnoses were revised prior to molecular testing. Eighty‐one patients (82%) underwent genetic testing, including 43 exome‐based panels, 15 whole‐genome sequencing, 14 single gene tests, 27 repeat‐primed polymerase chain reaction testing and two chromosomal microarrays. Overall, 33/99 patients (33%) received a diagnosis, either a molecular diagnosis (n = 24, of which 22 were diagnostic and two were predictive) or a clinical diagnosis (n = 9). Of the clinical diagnosis cohort, five patients received a diagnosis without molecular testing and four patients whose negative testing (one diagnostic and three predictive) allowed exclusion of genetic differentials and, hence, confirmation of clinical diagnoses. The diagnostic rate following MDT and diagnostic testing was 30% (28/94), excluding the five predictive testing cases. MDT assessment aligned with eventual molecular diagnoses in 96% of cases. The estimated average costs were AU$1386 per patient undergoing MDT assessment and AU$4159 per diagnosis achieved.ConclusionsWe present an integrated multidisciplinary neurogenomics clinic pathway providing a diagnostic yield of 33% (30% excluding predictive testing cases), with costing implications. The relatively high diagnostic yield may be attributed to multidisciplinary input integrating accurate phenotyping of complex disorders and interpretation of genomic findings.

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Section: Discussionsupporting

confidence: 62%

Informing a value care model: lessons from an integrated adult neurogenomics clinic

McLean

Tchan

Devery

et al. 2023

Internal Medicine Journal

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“…In a study of whole genome sequencing in 100 generally healthy pa1ents aged 40-65 years in the primary care seong, Vassy et al discovered a new gene1c diagnosis in 22%, 16 although many pa1ents exhibited only minimal symptoms of their diagnosis. In other studies of adult pa1ents with suspicion for a gene1c diagnosis, 14,15,[17][18][19] the diagnos1c rate of exome sequencing has been reported to range from 14-29% -lower than that observed in the pediatric popula1on, 25 but high enough to demonstrate the u1lity of broad gene1c tes1ng approaches in adults. The diagnos1c rate of 24% that we report in our study is in keeping with these previous reports, despite the fact that the popula1on we examined was not specifically selected for suspicion of gene1c disease.…”

Section: Discussionmentioning

confidence: 94%

“…many patients exhibited only minimal symptoms of their diagnosis. In other studies of adult patients with suspicion for a genetic diagnosis,14,15,[17][18][19] …”

mentioning

confidence: 99%

Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing

Gold,

Kripke,

Drivas

2024

Preprint

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Numerous studies have underscored the diagnostic and therapeutic potential of exome or genome sequencing in critically ill pediatric populations. However, an equivalent investigation in critically ill adults remains conspicuously absent. We retrospectively analyzed whole exome sequencing (WES) data available through the PennMedicine Biobank (PMBB) from all 365 young adult patients, aged 18-40 years, with intensive care unit (ICU) admissions at the University of Pennsylvania Health System who met inclusion criteria for our study. For each participant, two Medical Genetics and Internal Medicine-trained clinicians reviewed WES reports and patient charts for variant classification, result interpretation, and identification of genetic diagnoses related to their critical illness. Of the 365 individuals in our study, 90 (24.7%) were found to have clearly diagnostic results on WES; an additional 40 (11.0%) had a suspicious variant of uncertain significance (VUS) identified; and an additional 16 (4.4%) had a medically actionable incidental finding. The diagnostic rate of exome sequencing did not decrease with increasing patient age. Affected genes were primarily involved in cardiac function (18.8%), vascular health (16.7%), cancer (16.7%), and pulmonary disease (11.5%). Only half of all diagnostic findings were known and documented in the patient chart at the time of ICU admission. Significant disparities emerged in subgroup analysis by EHR-reported race, with genetic diagnoses known/documented for 63.5% of White patients at the time of ICU admission but only for 28.6% of Black or Hispanic patients. There was a trend towards patients with undocumented genetic diagnoses having a 66% increased mortality rate, making these race-based disparities in genetic diagnosis even more concerning. Altogether, universal exome sequencing in ICU-admitted adult patients was found to yield a new definitive diagnosis in 11.2% of patients. Of these diagnoses, 76.6% conferred specific care-altering medical management recommendations. Our study suggests that the diagnostic utility of exome sequencing in critically ill young adults is similar to that observed in neonatal and pediatric populations and is age-independent. The high diagnostic rate and striking race-based disparities we find in genetic diagnoses argue for broad and universal approaches to genetic testing for critically ill adults. The widespread implementation of comprehensive genetic sequencing in the adult population promises to enhance medical care for all individuals and holds the potential to rectify disparities in genetic testing referrals, ultimately promoting more equitable healthcare delivery.

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“…Almost 100 individuals with suspected or confirmed MED13L haploinsufficiency syndrome have been reported to date [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. According to the DECIPHER database, there are additional pathogenic MED13L deletions and duplications.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterisation of a Novel Intragenic 12q24.21 Deletion Resulting in MED13L Haploinsufficiency Syndrome

et al. 2023

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Background and Objectives: Heterozygous pathogenic variants in the MED13L gene cause impaired intellectual development and distinctive facial features with or without cardiac defects (MIM #616789). This complex neurodevelopmental disorder is characterised by various phenotypic features, including plagiocephaly, strabismus, clubfoot, poor speech, and developmental delay. The aim of this study was to evaluate the clinical significance and consequences of a novel heterozygous intragenic MED13L deletion in a proband with clinical features of a MED13L-related disorder through extensive clinical, molecular, and functional characterisation. Materials and Methods: Combined comparative genomic hybridisation and single-nucleotide polymorphism array (SNP-CGH) was used to identify the changes in the proband’s gDNA sequence (DECIPHER #430183). Intragenic MED13L deletion was specified via quantitative polymerase chain reaction (qPCR) and Sanger sequencing of the proband’s cDNA sample. Western blot and bioinformatics analyses were used to investigate the consequences of this copy number variant (CNV) at the protein level. CRISPR-Cas9 technology was used for a MED13L-gene-silencing experiment in a culture of the control individual’s skin fibroblasts. After the MED13L-gene-editing experiment, subsequent functional fibroblast culture analyses were performed. Results: The analysis of the proband’s cDNA sample allowed for specifying the regions of the breakpoints and identifying the heterozygous deletion that spanned exons 3 to 10 of MED13L, which has not been reported previously. In silico, the deletion was predicted to result in a truncated protein NP_056150.1:p.(Val104Glyfs*5), partly altering the Med13_N domain and losing the MedPIWI and Med13_C domains. After MED13L gene editing was performed, reduced cell viability; an accelerated aging process; and inhibition of the RB1, E2F1, and CCNC gene expression were found to exist. Conclusions: Based on these findings, heterozygous intragenic 12q24.21 deletion in the affected individual resulted in MED13L haploinsufficiency due to the premature termination of protein translation, therefore leading to MED13L haploinsufficiency syndrome.

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

Cited by 8 publications

References 16 publications

Informing a value care model: lessons from an integrated adult neurogenomics clinic

Informing a value care model: lessons from an integrated adult neurogenomics clinic

Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing

Molecular and Functional Characterisation of a Novel Intragenic 12q24.21 Deletion Resulting in MED13L Haploinsufficiency Syndrome

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