Rapid whole-genome sequencing identifies a novel homozygous <i>NPC1</i> variant associated with Niemann–Pick type C1 disease in a 7-week-old male with cholestasis

Hildreth, Amber; Wigby, Kristen; Chowdhury, Shimul; Nahas, Shareef; Barea, Jaime; Ordonez, Paulina; Batalov, Serge; Dimmock, David

doi:10.1101/mcs.a001966

Cited by 14 publications

(23 citation statements)

References 25 publications

(26 reference statements)

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“…rWGS revealed a diagnosis of Niemann-Pick disease, type C1 (NPC1). He started treatment with miglustat with plans for intrathecal cyclodextran and remains without neurologic symptoms(11). Using a modified Delphi method, the consensus of an international panel of paediatricians was that, had rWGS been performed on his first admission, the second admission would have been unnecessary.…”

Section: Impact Of Rwgs-associated Precision Medicine On Healthcare Umentioning

confidence: 99%

Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

Farnaes

Hildreth

Sweeney

et al. 2018

Preprint

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BACKGROUNDGenetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.METHODSRetrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.FINDINGSThe diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.DISCUSSIONThese findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

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Section: Impact Of Rwgs-associated Precision Medicine On Healthcare Umentioning

confidence: 99%

Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

Farnaes

Hildreth

Sweeney

et al. 2018

Preprint

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“…decrease morbidity and mortality 5,6,[21][22][23][24] . In two prior studies of genomic sequencing in infants, genetic diagnoses led to precision medicine that was considered life-saving in 5%, and that avoided major morbidity in 6% 6,7 .…”

Section: The Rationale For Rwgs In Nicu Infants Is To Enable Considermentioning

confidence: 99%

“…Amongst high-cost health care, NICU treatment is one of the most cost-effective [17][18][19] . Since disease progression can be very rapid in infants, genetic diagnoses must be made quickly to permit consideration of precision interventions in time to decrease morbidity and mortality 5,6,[20][21][22][23] . For a few genetic diseases, newborn screening has shown early neonatal diagnosis and rapid, precise intervention to dramatically improve outcomes 24,25 .…”

Section: Introductionmentioning

confidence: 99%

“…There is substantial evidence that a higher proportion of symptomatic children with likely genetic disease receive etiologic diagnoses by WGS and WES than other genetic tests [3][4][5][6][7]6,[28][29][30][31][32][33][34][35] . Published NICU or PICU experience with rWGS, however, is limited to case reports and one retrospective study 5,6,[20][21][22][23] . In the latter, 57% of infants received genetic diagnoses in a median of 23 days (day of life 49) 6 .…”

Section: Introductionmentioning

confidence: 99%

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The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

Petrikin

Cakici

Clark

et al. 2017

Preprint

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ImportanceGenetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.ObjectiveTo test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.DesignAn investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.SettingA regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.ParticipantsSixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.InterventionParent and infant trio rWGS.Main Outcome and MeasureThe hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.ResultsTwenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).CONCLUSIONSrWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.

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“…1,2,4,7 Of the 'omics technologies, genomics was the first to be accepted in the clinical space. [20][21][22][23][24][25][26][27][28][29][30] Metabolomics, a term introduced in 1998, 31 is a relatively newer technology that has been used increasingly over the past decade ( Figure 1) and may be utilized to screen for and to identify the cause of disease.…”

Section: Introductionmentioning

confidence: 99%

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

et al. 2018

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Metabolomics is the untargeted measurement of the metabolome, which is composed of the complement of small molecules detected in a biological sample. As such, metabolomic analysis produces a global biochemical phenotype. It is a technology that has been utilized in the research setting for over a decade. The metabolome is directly linked to and is influenced by genetics, epigenetics, environmental factors, and the microbiome—all of which affect health. Metabolomics can be applied to human clinical diagnostics and to other fields such as veterinary medicine, nutrition, exercise, physiology, agriculture/plant biochemistry, and toxicology. Applications of metabolomics in clinical testing are emerging, but several aspects of its use as a clinical test differ from applications focused on research or biomarker discovery and need to be considered for metabolomics clinical test data to have optimum impact, be meaningful, and be used responsibly. In this review, we deconstruct aspects and challenges of metabolomics for clinical testing by illustrating the significance of test design, accurate and precise data acquisition, quality control, data processing, n‐of‐1 comparison to a reference population, and biochemical pathway analysis. We describe how metabolomics technology is integral to defining individual biochemical phenotypes, elaborates on human health and disease, and fits within the precision medicine landscape. Finally, we conclude by outlining some future steps needed to bring metabolomics into the clinical space and to be recognized by the broader medical and regulatory fields.

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Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann–Pick type C1 disease in a 7-week-old male with cholestasis

Cited by 14 publications

References 25 publications

Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

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