Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield

Gubbels, Cynthia S.; VanNoy, Grace E.; Madden, Jill A.; Copenheaver, Deborah; Yang, Sandra; Wojcik, Monica H.; Gold, Nina B.; Genetti, Casie A.; Stoler, Joan M.; Parad, Richard B.; Rumyantsev, S. A.; Bodamer, Olaf A.; Beggs, Alan H.; Juusola, Jane; Agrawal, Pankaj B.; Yu, Timothy W.

doi:10.1038/s41436-019-0708-6

Cited by 99 publications

(100 citation statements)

References 39 publications

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“…In practice, the choice of the underlying assay is often linked with workflow, since post hoc filtering allows for the creation of a virtual gene panel. A larger group of conditions that have non-specific clinical and biochemical phenotypes, such as many of the mitochondrial disorders, untargeted and semi-targeted NGS, are currently the de facto second-tier investigation [50]. In the absence of family history, molecular testing is usually confirmatory.…”

Section: Confirmatory Diagnostic Testingmentioning

confidence: 99%

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

Mordaunt

Cox

Fuller

2020

IJMS

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Early diagnosis of inborn errors of metabolism (IEM)—a large group of congenital disorders—is critical, given that many respond well to targeted therapy. Newborn screening programs successfully capture a proportion of patients enabling early recognition and prompt initiation of therapy. For others, the heterogeneity in clinical presentation often confuses diagnosis with more common conditions. In the absence of family history and following clinical suspicion, the laboratory diagnosis typically begins with broad screening tests to circumscribe specialised metabolite and/or enzyme assays to identify the specific IEM. Confirmation of the biochemical diagnosis is usually achieved by identifying pathogenic genetic variants that will also enable cascade testing for family members. Unsurprisingly, this diagnostic trajectory is too often a protracted and lengthy process resulting in delays in diagnosis and, importantly, therapeutic intervention for these rare conditions is also postponed. Implementation of mass spectrometry technologies coupled with the expanding field of metabolomics is changing the landscape of diagnosing IEM as numerous metabolites, as well as enzymes, can now be measured collectively on a single mass spectrometry-based platform. As the biochemical consequences of impaired metabolism continue to be elucidated, the measurement of secondary metabolites common across groups of IEM will facilitate algorithms to further increase the efficiency of diagnosis.

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Section: Confirmatory Diagnostic Testingmentioning

confidence: 99%

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

Mordaunt

Cox

Fuller

2020

IJMS

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“…With NGS, large panels of genes can be rapidly scanned at the same time, at a much lower cost, and with a higher probability of an accurate diagnosis. Exome and genome sequencing (ES/GS) are increasingly being used to accelerate diagnosis in the neonatal intensive care unit (NICU), and some studies have found diagnostic yields in the 21-60% range (Gubbels et al, 2019). Still, it remains unclear which patients are most likely to derive optimal benefi t from ES/GS sequencing, because enrollment criteria in studies tend to rely on expert opinions from specialized teams typically composed of medical and metabolic geneticists and neurologists.…”

Section: Research Update Continuedmentioning

confidence: 99%

“…Thus, as the use of ES/GS continues to expand in the NICU, it becomes increasingly important to defi ne which patients will derive the most benefi t, especially in facilities with limited access to geneticists and other experts. In a new study, researchers have now developed and tested phenotype-based criteria for selecting NICU patients for rapid-turnaround ES as a fi rst-line test (Gubbels et al, 2019). The method allowed for an overall diagnostic yield of 58%, which was comparable to, or even higher than, those observed in studies using expert-driven patient selection.…”

Section: Research Updatementioning

confidence: 99%

Phenotype‐Based Criteria Increases Diagnostic Impact of Exome Sequencing in Neonates

2020

American J of Med Genetics Pt A

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“…Over the past 5 years, rapid genomic sequencing has demonstrated consistent utility in this population. In 873 children in ICUs described in 13 studies, 36% received a genetic disease diagnosis by rapid genomic sequencing 17 , 20 , 21 , 23 – 26 , 28 , 30 , 33 , 34 , 36 , 38 – 45 . The average clinical or therapeutic utility of those diagnoses was 71%.…”

Section: Introductionmentioning

confidence: 99%

Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing

et al. 2020

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Understanding causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. Rapid genomic sequencing has created a novel opportunity to decrease infant mortality associated with treatable genetic diseases. Herein, we sought to measure the contribution of genetic diseases to mortality among infants by secondary analysis of babies enrolled in two clinical studies and a systematic literature review. Among 312 infants who had been admitted to an ICU at Rady Children’s Hospital between November 2015 and September 2018 and received rapid genomic sequencing, 30 (10%) died in infancy. Ten (33%) of the infants who died were diagnosed with 11 genetic diseases. The San Diego Study of Outcomes in Mothers and Infants platform identified differences between in-hospital and out-of-hospital causes of infant death. Similarly, in six published studies, 195 (21%) of 918 infant deaths were associated with genetic diseases by genomic sequencing. In 195 infant deaths associated with genetic diseases, locus heterogeneity was 70%. Treatment guidelines existed for 70% of the genetic diseases diagnosed, suggesting that rapid genomic sequencing has substantial potential to decrease infant mortality among infants in ICUs. Further studies are needed in larger, comprehensive, unbiased patient sets to determine the generalizability of these findings.

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Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield

Cited by 99 publications

References 39 publications

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

Phenotype‐Based Criteria Increases Diagnostic Impact of Exome Sequencing in Neonates

Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing

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