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

ABSTRACT: PURPOSE:To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria. METHODS:Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team. RESULTS:A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies. CONCLUSION:Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.

SUBMITTER: Gubbels CS

PROVIDER: S-EPMC7127968 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Gubbels Cynthia S CS VanNoy Grace E GE Madden Jill A JA Copenheaver Deborah D Yang Sandra S Wojcik Monica H MH Gold Nina B NB Genetti Casie A CA Stoler Joan J Parad Richard B RB Roumiantsev Sergei S Bodamer Olaf O Beggs Alan H AH Juusola Jane J Agrawal Pankaj B PB Yu Timothy W TW

Genetics in medicine : official journal of the American College of Medical Genetics 20191129 4

<h4>Purpose</h4>To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria.<h4>Methods</h4>Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team.<h4>Results</h4>A genetic ...[more]

PMID: 31780822

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Project description: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 HER-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.

Project description:BackgroundPulmonary infiltrates of variable etiology are one of the main reasons for hypoxemic respiratory failure leading to invasive mechanical ventilation. If pulmonary infiltrates remain unexplained or progress despite treatment, the histopathological result of a lung biopsy could have significant impact on change in therapy. Surgical lung biopsy is the commonly used technique, but due to its considerable morbidity and mortality, less invasive bronchoscopic transbronchial lung biopsy (TBLB) may be a valuable alternative.MethodsRetrospective, monocentric, observational study in mechanically ventilated, critically ill patients, subjected to TBLB due to unexplained pulmonary infiltrates in the period January 2014 to July 2019. Patients' medical records were reviewed to obtain data on baseline clinical characteristics, modality and adverse events (AE) of the TBLB, and impact of the histopathological results on treatment decisions. A multivariable binary logistic regression analysis was performed to identify predictors of AE and hospital mortality, and survival curves were generated using the Kaplan-Meier method.ResultsForty-two patients with in total 42 TBLB procedures after a median of 12 days of mechanical ventilation were analyzed, of which 16.7% were immunosuppressed, but there was no patient with prior lung transplantation. Diagnostic yield of TBLB was 88.1%, with AE occurring in 11.9% (most common pneumothorax and minor bleeding). 92.9% of the procedures were performed as a forceps biopsy, with organizing pneumonia (OP) as the most common histological diagnosis (54.8%). Variables independently associated with hospital mortality were age (odds ratio 1.070, 95%CI 1.006-1.138; p = 0.031) and the presence of OP (0.182, [0.036-0.926]; p = 0.040), the latter being confirmed in the survival analysis (log-rank p = 0.040). In contrast, a change in therapy based on histopathology alone occurred in 40.5%, and there was no evidence of improved survival in those patients.ConclusionsTransbronchial lung biopsy remains a valuable alternative to surgical lung biopsy in mechanically ventilated critically ill patients. However, the high diagnostic yield must be weighed against potential adverse events and limited consequence of the histopathological result regarding treatment decisions in such patients.

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

Publications

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

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