Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations

Chung, Claudia C.Y.; Hue, Shirley P.Y.; Ng, Nicole Y.T.; Doong, Phoenix H.L.; Chu, Annie T.W.; Chung, Brian H.Y.

doi:10.1016/j.gim.2023.100896

Cited by 24 publications

(19 citation statements)

References 180 publications

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“…discovered a new genetic diagnosis in 22%, 16 although many patients exhibited only minimal symptoms of their diagnosis. In other studies of adult patients with suspicion for a genetic diagnosis, 14,15,17–19 the diagnostic rate of exome sequencing has been reported to range from 14-29% – lower than that observed in the pediatric population, 25 but high enough to demonstrate the utility of broad genetic testing approaches in adults. The diagnostic rate of 24% that we report in our study is in keeping with these previous reports, despite the fact that the population we examined was not specifically selected for suspicion of genetic disease.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…Participation was limited to individuals with signs or symptoms indicative of a RGD, consistent with current professional guidelines and prior large RGD population investigations, and limited access to molecular testing. 7,9,14,15 Cohort characteristics A total of 1,004 individuals from 981 families received cGS testing through the iHope program from June 2016 through September 2021 (Fig. 1 and Supplementary Table 1), thirty-four percent (345/1004) of which were from LMIC sites including Mexico (209), Peru (89), the Democratic Republic of Congo (35), Ghana (9) and individual cases from Romania (1), Brazil (1) and India (1) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The diagnostic yield of cGS across the cohort was comparable to similar studies in genetically and phenotypically diverse cohorts but was increased in LMIC compared to HIC patients. 7,8,14 Some of this difference may be explained by differential test utilization as patients from HIC sites were 6.6times more likely than patients from LMIC sites to have had at least one prior genetic test, suggesting that cGS in the LMIC population was more often utilized as a rst-line test, potentially in patients with more severe phenotypic presentations. This hypothesis is supported by cGS detection of an increased number and size of copy number variants in the LMIC population, which may have been identi ed by chromosomal microarray or karyotype if otherwise available.…”

Section: Discussionmentioning

confidence: 99%

The impact of clinical genome sequencing in a global population of patients with suspected rare genetic disease

Taft,

Thorpe,

Williams

et al. 2023

Preprint

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Clinical genome sequencing (cGS) holds promise as a unified diagnostic testing platform in patients with a suspected rare genetic disease (RGD), however its performance and impact on clinical management in a diverse global population has yet to be investigated. The iHope program established a network of 24 clinical sites in eight countries to provide cGS to individuals with signs or symptoms of a RGD and constrained access to molecular testing. A retrospective, observational analysis of 1,004 individuals who received cGS testing from June 2016 through September 2021 was performed. The cGS diagnostic yield in this diverse cohort (51.8% non-majority European) was 41.4% (416/1004), with patients from sites in low- and middle-income countries (LMIC) 2.6-times more likely to receive a positive test result compared to sites in high-income countries (HIC) (95% CI 1.9–3.4, p < 0.0001). Changes in diagnostic evaluation and management were reported in 76.9% and 69.2% of cases, respectively. Comparison of LMIC and HIC patients with positive test results demonstrated that LMIC patients were equally likely to experience a change in DE (OR 6.1, 95% CI 1.1- , p = 0.05) and COM (OR 0.9, 95% CI 0.5–1.3, p = 0.49), indicating that increased access to cGS may support diagnostic equity and the reduction of global health care disparities.

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“…Besides, receiving a negative or inconclusive genetic test result is not uncommon. Deep phenotyping has been demonstrated an important role in improving diagnostic yield [ 26 – 30 ]. Physicians specialized in relevant field are recommended to participate in the pre-testing phenotyping, collaborating and communicating under an MDT framework, to provide accurate phenotypic description.…”

Section: The Recommendationsmentioning

confidence: 99%

Diagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines

Xu,

Li,

et al. 2024

Orphanet J Rare Dis

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Background The Ehlers-Danlos syndromes (EDS) are a group of rare hereditary connective tissue disorders. EDS is clinically and genetically heterogeneous and usually involves multiple systems. There are 14 subtypes of EDS with hallmark features including joint hypermobility, skin hyperextensibility, and tissue fragility. The clinical manifestations and their severity differ among the subtypes, encompassing recurrent joint dislocations, scoliosis, arterial aneurysm and dissection, and organ rupture. Challenges in diagnosis and management arise from the complexity of the disease, which is further complicated by its rarity. The development of clinical guidelines and implementation of coordinated multi-disciplinary team (MDT) approaches have emerged as global priorities. Main body Chinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes was therefore established. Healthcare professionals were recruited from 25 top hospitals across China. The experts are specialized in 24 fields, including genetics, vascular surgery, dermatology, and orthopedics, as well as nursing care, rehabilitation, psychology, and nutrition. Based on GRADE methodology, the Guidelines were written by the Group supervised by methodologists, following a systemic review of all 4453 articles in PubMed published before August 9, 2023, using the search term “Ehlers Danlos”. A coordinated MDT approach for the diagnosis and management of EDS is highly recommended by the Group, along with 29 specific recommendations addressing key clinical questions. In addition to the treatment plan, the Guidelines also emphasize integrating support from nursing care, rehabilitation, psychology, and nutrition. This integration not only facilitates recovery in hospital settings, but most importantly, the transition from an illness-defined life to a more “normalized” life. Conclusion The first guidelines on EDS will shorten the diagnostic odyssey and solve the unmet medical needs of the patients. This article is a synopsis of the full guidelines.

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Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations

Cited by 24 publications

References 180 publications

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

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

The impact of clinical genome sequencing in a global population of patients with suspected rare genetic disease

Diagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines

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