Diagnostic sequencing to support genetically stratified medicine in a tertiary care setting

Lippa, Natalie; Bier, Louise; Revah‐Politi, Anya; May, Halie; Kushary, Sulagna; Vena, Natalie; Giordano, Jessica L.; Rasouly, Hila Milo; Cocchi, Enrico; Sands, Tristan T.; Wapner, Ronald J.; Anyane‐Yeboa, Kwame; Gharavi, Ali G.; Goldstein, David B.

doi:10.1016/j.gim.2021.12.010

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…The diagnostic analysis and outcomes of the MSCH cohort are a subset of the cohort reported by Lippa and colleagues. 30 Briefly, trio or proband-only ES analysis was completed. Candidate genotypes were reviewed with the research team and clinical team to reach a consensus interpretation.…”

Section: Methodsmentioning

confidence: 99%

Children with Critical Illness Carry Risk Variants Despite Non-Diagnostic Whole Exome Sequencing

Motelow

Lippa

Hostyk

et al. 2022

Preprint

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Rapid genetic sequencing is an established and important clinical tool for management of pediatric critical illness. The burden of risk variants in children with critical illness but a non–diagnostic exome has not been explored. This was a retrospective case–control analysis of research whole exome sequencing data that first underwent a diagnostic pipeline to assess the association of rare loss–of–function variants with critical illness in children with diagnostic and non-diagnostic whole exome sequencing including those with virally mediated respiratory failure. Using a gene–based collapsing approach, the odds of a child with critical illness carrying rare loss–of–function variants were compared to controls. A subset of children with virally mediated respiratory failure was also compared to controls. Cases were drawn from the general pediatric ward and pediatric intensive care unit (PICU) at Morgan Stanley Childrens Hospital of NewYork–Presbyterian (MSCH) – Columbia University Irving Medical Center (CUIMC) and from the Office of the Chief Medical Examiner (OCME) of New York City. Of the 285 enrolled patients, 228 did not receive a diagnosis from WES. After quality control filtering and geographic ancestry matching, an analysis of 232 children with critical illness compared to 5,322 healthy and unrelated controls determined cases to harbor more predicted loss–of–function (pLOFs) in genes with a LOEUF score ≤ 0.680 (p–value = 1.0 x 10–5). After quality control and geographic ancestry matching, a subset of 176 children without a genetic diagnosis compared to 5,180 controls harbored pLOFs in genes without a disease association (OR 1.7, CI [1.2 – 2.3], FDR adjusted p–value = 4.4 x 10–3) but not in genes with a disease association (OR 1.2, CI [0.8 – 1.7], FDR adjusted p–value = 0.40). This enrichment primarily existed among ultra–rare variants not found in public data sets. Among a subset of 25 previously healthy children with virally mediated respiratory failure compared to 2,973 controls after quality control and geographic ancestry matching, cases harbored more variants than controls in genes without a disease association at the same LOEUF threshold ≤ 0.680 (OR 2.8, CI [1.2 – 7.2], FDR adjusted p–value = 0.026) but not in genes with a disease association (OR 0.7, CI [0.2 – 2.2], FDR adjusted p–value = 0.84). Finally, children with critical illness for whom whole exome sequencing data from both biological parents were available, we found an enrichment of de novo pLOF variants in genes without a disease association among 114 children without a genetic diagnosis (unadjusted p–value < 0.05) but not among 46 children with a genetic diagnosis. Children with critical illness and non–diagnostic whole exome sequencing may still carry risk variants for their clinical presentation in genes not previously associated with disease.

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Section: Methodsmentioning

confidence: 99%

Children with Critical Illness Carry Risk Variants Despite Non-Diagnostic Whole Exome Sequencing

Motelow

Lippa

Hostyk

et al. 2022

Preprint

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“…The Columbia University Institutional Review Board approved protocols, and written informed consent was provided for using DNA in genetic research at the IGM at CUIMC. 27 Individuals enrolled at the MSCH were referred by their CUIMC clinician. Written informed consent was provided by the legal guardian for participants younger than 18 years or by the individual when 18 years or older.…”

Section: Methodsmentioning

confidence: 99%

“…The diagnostic analysis of the MSCH cohort is a subset of that reported by Lippa et al 27 Briefly, trio (ie, ES available from proband and both biological parents) or proband-only ES analyses were completed. Candidate genotypes were reviewed with the research and clinical teams to reach consensus.…”

Section: Methodsmentioning

confidence: 99%

“…Controls were individuals with data at the Institute for Genomic Medicine (IGM) enrolled as controls (n = 3358) or healthy family members (n = 6632) across multiple studies. The Columbia University Institutional Review Board approved protocols, and written informed consent was provided for using DNA in genetic research at the IGM at CUIMC . Individuals enrolled at the MSCH were referred by their CUIMC clinician.…”

Section: Methodsmentioning

confidence: 99%

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Risk Variants in the Exomes of Children With Critical Illness

et al. 2022

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ImportanceDiagnostic genetic testing can lead to changes in management in the pediatric intensive care unit. Genetic risk in children with critical illness but nondiagnostic exome sequencing (ES) has not been explored.ObjectiveTo assess the association between loss-of-function (LOF) variants and pediatric critical illness.Design, Setting, and ParticipantsThis genetic association study examined ES first screened for causative variants among 267 children at the Morgan Stanley Children’s Hospital of NewYork-Presbyterian, of whom 22 were otherwise healthy with viral respiratory failure; 18 deceased children with bronchiolitis from the Office of the Chief Medical Examiner of New York City, of whom 14 were previously healthy; and 9990 controls from the Institute for Genomic Medicine at Columbia University Irving Medical Center. The ES data were generated between January 1, 2015, and December 31, 2020, and analyzed between January 1, 2017, and September 2, 2022.ExposureCritical illness.Main Outcomes and MeasuresOdds ratios and P values for genes and gene-sets enriched for rare LOF variants and the loss-of-function observed/expected upper bound fraction (LOEUF) score at which cases have a significant enrichment.ResultsThis study included 285 children with critical illness (median [range] age, 4.1 [0-18.9] years; 148 [52%] male) and 9990 controls. A total of 228 children (80%) did not receive a genetic diagnosis. After quality control (QC), 231 children harbored excess rare LOF variants in genes with a LOEUF score of 0.680 or less (intolerant genes) (P = 1.0 × 10−5). After QC, 176 children without a diagnosis harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 1.8; 95% CI, 1.3-2.5). After QC, 25 children with viral respiratory failure harbored excess ultrarare LOF variants in intolerant genes but only in those without a known disease association (odds ratio, 2.8; 95% CI, 1.1-6.6). A total of 114 undiagnosed children were enriched for de novo LOF variants in genes without a known disease association (observed, 14; expected, 6.8; enrichment, 2.05).Conclusions and RelevanceIn this genetic association study, excess LOF variants were observed among critically ill children despite nondiagnostic ES. Variants lay in genes without a known disease association, suggesting future investigation may connect phenotypes to causative genes.

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“…CLIA-confirmed variants were returned to referring providers and subsequently returned to participants, a process that has been described previously. 27 The current study included participants in this broad epilepsy protocol who were 18 years of age and younger at the time of enrollment and who were deemed to have received a causative variant for their phenotype from the research ES. Participants with only secondary findings unrelated to their epilepsy phenotype were not included.…”

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confidence: 99%

Clinical utility of exome sequencing in a pediatric epilepsy cohort

et al. 2023

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Objective Exome sequencing (ES) has played an important role in the identification of causative variants for individuals with epilepsy and has proven to be a valuable diagnostic tool. Less is known about its clinical utility once a diagnosis is received. This study systematically reviewed the impact of ES results on clinical decision‐making and patient care in a pediatric epilepsy cohort at a tertiary care medical center. Methods Pediatric patients with unexplained epilepsy were referred by their neurologist, and informed consent was obtained through an institutional review board–approved research ES protocol. For patients who received a genetic diagnosis, a retrospective chart review was completed of the probands and their relatives' medical records prior to and after genetic diagnosis. The following outcomes were explored: provider management recommendations, changes in care actually implemented, and anticipatory guidance provided regarding the proband's condition. Results Fifty‐three probands met the inclusion criteria. Genetic diagnosis led to at least one provider recommendation in 41.5% families (22/53). Recommendations were observed in the following categories: medication, screening for non‐neurological comorbidities/referrals to specialists, referrals to clinical research/trials, and cascade testing. Anticipatory guidance including information about molecular diagnosis, prognosis, and relevant foundations/advocacy groups was also observed. Significance Results demonstrate the clinical utility of ES for individuals with epilepsy across multiple aspects of patient care, including anti‐seizure medication (ASM) selection; screening for non‐neurological comorbidities and referrals to appropriate medical specialists; referral to reproductive genetic counseling; and access to research, information, and support resources. To our knowledge, this is the first study to evaluate the clinical utility of ES for a pediatric epilepsy cohort with broad epilepsy phenotypes. This work supports the implementation of ES as part of clinical care in this population.

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Diagnostic sequencing to support genetically stratified medicine in a tertiary care setting

Cited by 7 publications

References 26 publications

Children with Critical Illness Carry Risk Variants Despite Non-Diagnostic Whole Exome Sequencing

Children with Critical Illness Carry Risk Variants Despite Non-Diagnostic Whole Exome Sequencing

Risk Variants in the Exomes of Children With Critical Illness

Clinical utility of exome sequencing in a pediatric epilepsy cohort

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