Scientific Publications

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12 Results

2021

Rapid whole genome sequencing in critically ill children: Shifting from unease to evidence, education and equitable implementation

Linda S. Franck, RN, PhD, David Dimmock, MD, FACMG DABP, Charlotte Hobbs, MD, PhD, Stephen F. Kingsmore, MD, DSc

J Pediatr. 2021 Aug 11:S0022-3476(21)00761-7. doi: 10.1016/j.jpeds.2021.08.006. Online ahead of print. NO ABSTRACT PMID:34390697 | DOI:10.1016/j.jpeds.2021.08.006

August 17, 2021
rWGS

Postmortem whole-genome sequencing on a dried blood spot identifies a novel homozygous SUOX variant causing isolated sulfite oxidase deficiency

Owen MJ, Lenberg J, Feigenbaum A, Gold J, Chau K, Bezares-Orin Z, Ding Y, Chowdhury S, Kingsmore SF. 

Cold Spring Harb Mol Case Stud. 2021 Jun 11;7(3):a006091. doi: 10.1101/mcs.a006091. Print 2021 Jun. ABSTRACT Rapid whole-genome sequencing (rWGS) has shown that genetic diseases are a common cause of infant mortality in neonatal intensive care units. Dried blood spots collected for newborn screening allow investigation of causes of infant mortality that were not diagnosed during life. Here, we present a neonate who developed seizures and encephalopathy on the third day of life that was refractory to antiepileptic medications. The patient died on day of life 16 after progressive respiratory failure and sepsis. The parents had lost two prior children after similar presentations, neither of whom had a definitive diagnosis. Postmortem rWGS of a dried blood spot identified a pathogenic homozygous frameshift variant in the SUOX gene associated with isolated sulfite oxidase deficiency (c.1390_1391del, p.Leu464GlyfsTer10). This case highlights that early, accurate molecular diagnosis has the potential to influence prenatal counseling and guide management in rare, genetic disorders and has added importance in cases of a strong family history and risk factors such as consanguinity. PMID:34117075 | DOI:10.1101/mcs.a006091

June 14, 2021
Infant MortalityrWGS

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care

Dimmock D, Caylor S, Waldman B, Benson W, Ashburner C, Carmichael JL, Carroll J, Cham E, Chowdhury S, Cleary J, D’Harlingue A, Doshi A, Ellsworth K, Galarreta CI, Hobbs C, Houtchens K, Hunt J, Joe P, Joseph M, Kaplan RH, Kingsmore SF, Knight J, Kochhar A, Kronick RG, Limon J, Martin M, Rauen KA, Schwarz A, Shankar SP, Spicer R, Rojas MA, Vargas-Shiraishi O, Wigby K, Zadeh N, Farnaes L. 

Am J Hum Genet. 2021 May 29:S0002-9297(21)00192-0. doi: 10.1016/j.ajhg.2021.05.008. Online ahead of print. ABSTRACT Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children’s hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear. PMID:34089648 | DOI:10.1016/j.ajhg.2021.05.008

June 7, 2021
RPM for NICU and PICUrWGS

Rapid Sequencing-Based Diagnosis of Thiamine Metabolism Dysfunction Syndrome

Owen MJ, Niemi AK, Dimmock DP, Speziale M, Nespeca M, Chau KK, Van Der Kraan L, Wright MS, Hansen C, Veeraraghavan N, Ding Y, Lenberg J, Chowdhury S, Hobbs CA, Batalov S, Zhu Z, Nahas SA, Gilmer S, Knight G, Lefebvre S, Reynders J, Defay T, Weir J, Thomson VS, Fraser L, Lajoie BR, McPhail TK, Mehtalia SS, Kunard CM, Hall KP, Kingsmore SF.

N Engl J Med. 2021 Jun 3;384(22):2159-2161. doi: 10.1056/NEJMc2100365. NO ABSTRACT PMID:34077649 | DOI:10.1056/NEJMc2100365

June 3, 2021
rWGS

Implementing Rapid Whole Genome Sequencing in Critical Care: A Qualitative Study of Facilitators and Barriers to New Technology Adoption

Franck LS, Kriz RM, Rego S, Garman K, Hobbs C, Dimmock D.

J Pediatr. 2021 May 20:S0022-3476(21)00496-0. doi: 10.1016/j.jpeds.2021.05.045. Online ahead of print. ABSTRACT OBJECTIVE: To characterize the views of members of the multi-disciplinary team regarding the implementation of Rapid Whole Genome Sequencing (rWGS) as a first-tier test for critically ill children in diverse children’s hospital settings. STUDY DESIGN: Qualitative interviews informed by implementation science theory were conducted with the multi-disciplinary patient care teams and hospital leaders at each of the five tertiary care children’s hospitals involved in a statewide rWGS implementation project. RESULTS: Our analysis revealed 5 key themes regarding the implementation process across the sites: the need for rWGS champions, educational needs and strategies, negotiating decision-making roles and processes, workflows and workarounds, and perceptions about rWGS. From the findings a composite clinical workflow diagram was developed to summarize all of the processes involved in the implementation of the test, and the key areas where implementation practices differed. CONCLUSIONS: These findings provide insights for design of interventions to support adoption, scale-up and sustainability of rWGS and other novel technologies in neonatal and pediatric critical care settings. PMID:34023348 | DOI:10.1016/j.jpeds.2021.05.045

May 24, 2021
rWGS

Expanding the genotypic spectrum of ACTG2-related visceral myopathy

James KN, Lau M, Shayan K, Lenberg J, Mardach R, Ignacio R Jr, Halbach J, Choi L, Kumar S, Ellsworth KA.

Cold Spring Harb Mol Case Stud. 2021 Apr 21:mcs.a006085. doi: 10.1101/mcs.a006085. Online ahead of print.

ABSTRACT

Visceral myopathies (VMs) encompass a spectrum of disorders characterized by chronic disruption of gastrointestinal function, with or without urinary system involvement. Pathogenic missense variation in smooth muscle gamma-actin gene (ACTG2) is associated with autosomal dominant VM. Whole genome sequencing of an infant presenting with chronic intestinal pseudo-obstruction revealed a homozygous 187 base pair (c.589_613+163del188) deletion spanning the exon 6-intron 6 boundary within ACTG2. The patient’s clinical course was marked by prolonged hospitalizations, multiple surgeries, and intermittent total parenteral nutrition dependence. This case supports the emerging understanding of allelic heterogeneity in ACTG2-related VM, in which both homozygous and heterozygous variants in ACTG2 are associated with gastrointestinal dysfunction of similar severity and overlapped clinical presentation. Moreover, it illustrates the clinical utility of rapid whole genome sequencing, which can comprehensively and precisely detect different types of genomic variants including small deletions, leading to guidance of clinical care decisions.

PMID:33883208 | DOI:10.1101/mcs.a006085

April 23, 2021
rWGS

Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease

Sweeney NM, Nahas SA, Chowdhury S, Batalov S, Clark M, Caylor S, Cakici J, Nigro JJ, Ding Y, Veeraraghavan N, Hobbs C, Dimmock D, Kingsmore SF. 

NPJ Genom Med. 2021 Apr 22;6(1):29. doi: 10.1038/s41525-021-00192-x.

ABSTRACT

Congenital heart disease (CHD) is the most common congenital anomaly and a major cause of infant morbidity and mortality. While morbidity and mortality are highest in infants with underlying genetic conditions, molecular diagnoses are ascertained in only ~20% of cases using widely adopted genetic tests. Furthermore, cost of care for children and adults with CHD has increased dramatically. Rapid whole genome sequencing (rWGS) of newborns in intensive care units with suspected genetic diseases has been associated with increased rate of diagnosis and a net reduction in cost of care. In this study, we explored whether the clinical utility of rWGS extends to critically ill infants with structural CHD through a retrospective review of rWGS study data obtained from inpatient infants < 1 year with structural CHD at a regional children’s hospital. rWGS diagnosed genetic disease in 46% of the enrolled infants. Moreover, genetic disease was identified five times more frequently with rWGS than microarray ± gene panel testing in 21 of these infants (rWGS diagnosed 43% versus 10% with microarray ± gene panels, p = 0.02). Molecular diagnoses ranged from syndromes affecting multiple organ systems to disorders limited to the cardiovascular system. The average daily hospital spending was lower in the time period post blood collection for rWGS compared to prior (p = 0.003) and further decreased after rWGS results (p = 0.000). The cost was not prohibitive to rWGS implementation in the care of this cohort of infants. rWGS provided timely actionable information that impacted care and there was evidence of decreased hospital spending around rWGS implementation.

PMID:33888711 | DOI:10.1038/s41525-021-00192-x

April 23, 2021
rWGS

2020

Diagnosis of cytomegalovirus infection from clinical whole genome sequencing

Ramchandar N, Ding Y, Farnaes L, Dimmock D, Hobbs C, Kingsmore SF, Bainbridge M. 

Sci Rep. 2020 Jul 3;10(1):11020. doi: 10.1038/s41598-020-67656-5. ABSTRACT Rapid whole genome sequencing (rWGS) of peripheral blood has been used to detect microbial DNA in acute infections. Cytomegalovirus (CMV) is a herpesvirus capable of causing severe disease in neonates and immunocompromised patients. We identified CMV in patients undergoing diagnostic rWGS by matching reads that did not align to the human reference genome to a database of microbial genomes. rWGS was conducted on peripheral blood obtained from ill pediatric patients (age 1 day to 18 years). Reads not aligning to the human genome were analyzed using an in-house pipeline to identify DNA consistent with CMV infection. Of 669 patients who received rWGS from July 2016 through July 2019, we identified 28 patients (4.2%) with reads that aligned to the CMV reference genome. Six of these patients had clinical findings consistent with symptomatic CMV infection. Positive results were highly correlated (R2 > 0.99, p < 0.001) to a CMV-qPCR assay conducted on DNA isolated from whole blood samples. In acutely ill children receiving rWGS for diagnosis of genetic disease, we propose analysis of patient genetic data to identify CMV, which could impact treatment of up to 4% of children in the intensive care unit. PMID:32620939 | PMC:PMC7335102 | DOI:10.1038/s41598-020-67656-5

July 5, 2020
Gene DiscoveryrWGS

Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system

Kingsmore SF, Ramchandar N, James K, Niemi AK, Feigenbaum A, Ding Y, Benson W, Hobbs C, Nahas S, Chowdhury S, Dimmock D. 

Cold Spring Harb Mol Case Stud. 2020 Feb 3;6(1):a004705. doi: 10.1101/mcs.a004705. Print 2020 Feb. ABSTRACT Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM. PMID:32014857 | PMC:PMC6996516 | DOI:10.1101/mcs.a004705

February 5, 2020
Infant MortalityrWGS

2019

Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU

Sanford EF, Clark MM, Farnaes L, Williams MR, Perry JC, Ingulli EG, Sweeney NM, Doshi A, Gold JJ, Briggs B, Bainbridge MN, Feddock M, Watkins K, Chowdhury S, Nahas SA, Dimmock DP, Kingsmore SF, Coufal NG; RCIGM Investigators.

Pediatr Crit Care Med. 2019 Nov;20(11):1007-1020. doi: 10.1097/PCC.0000000000002056. ABSTRACT OBJECTIVES: Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however, its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN: Retrospective cohort study. SETTING: Single-center PICU in a tertiary children’s hospital. PATIENTS: Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS: Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS: A molecular diagnosis was made by rapid whole genome sequencing in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS: This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear. PMID:31246743 | PMC:PMC6832787 | DOI:10.1097/PCC.0000000000002056

June 28, 2019
Infant MortalityrWGS

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