Rapid Precision Medicine

Our research and clinical work is focused on accelerating and optimizing the whole genome sequencing process to offer testing, analysis and interpretation of life-threatening genetic variations for newborns and children enrolled in one of our multi-center clinical studies.

Our primary focus has been on babies and children hospitalized in neonatal, pediatric or cardiovascular intensive care. In other cases, our studies focus on ending the diagnostic odyssey for stable pediatric patients who have been living with a rare disease, the cause of which has not been identified.

Change in Clinical Management to Improve Outcomes

Providing a rapid diagnosis is particularly important in cases where early intervention with a highly specific treatment, can prevent severe disability or death. Historically, testing for genetic disorders has been a lengthy, difficult process that rarely provided actionable data in time to change the patient’s medical management. Both positive (molecular diagnosis) and negative findings from rapid Whole Genome Sequencing™ (rWGS®) can inform optimal treatment of patients and also facilitate accurate, evidence-based discussions with the families of critically ill children in intensive care unit (ICU) settings.

Building the Evidence Base for rWGS

RCIGM research has contributed to 9 of 20 clinical trials demonstrating the utility of genome wide sequencing in children in intensive care settings.

The published evidence supporting the clinical utility of rapid Whole Genome Sequencing™ (rWGS®) and rapid whole exome sequencing (rWES) has increased rapidly.

PubMed IDSequence TypeNeonatal & Pediatric ICU Enrollment CriteriaPatientsDiagnosis RateClinical UtilityChange in Outcome
Indicates RCIGM publicationrWGS = rapid WGS | urWGS = ultra-rapid Whole Genome Sequencing | rWES = rapid Whole Exome Sequencing
23035047urWGS NICU infants with suspected genetic disease475%n.d.n.d.
25937001rWGS<4 mo of age; suspected actionable genetic disease3557%31%29%
28973083rWES<100 days of life; Suspected genetic disease6351%37%19%
29449963rWGS<4 mo of age; Suspected genetic disease3241%31%n.d.
29644095rWGSinfants; Suspected genetic disease4243%31%26%
29543227rWESAcutely ill children with suspected genetic diseases4053%30%8%
30049826rWGSChildren; PICU and Cardiovascular ICU2442%13%n.d.
31246743rWGS4 months-18 years; PICU; Suspected genetic diseases3848%39%8%
30847515rWGSSuspected genetic disease19521%13%n.d.
31019026urWGS Infants; Suspected genetic disease743%43%n.d.
31780822rWES<4 mo of age; ICU; hypotonia, seizures, metabolic, multiple congenital anomalies5054%48%n.d.
32411386rWESNICU & PICU; complex13048%23%n.d.
32553838rWES<6 months; ICU; suspected genetic disease4652%52%n.d.
32221475rWESPICU; < 6 years; new metabolic/neurologic disease1050%30%n.d.
32336750rWESInfants; ICU; Genetic consult36827%22%n.d.
32573669urWES NICU and PICU; Genetic counsult10851%44%n.d.
32668698rWESICU infants; Severe or progressive conditions1872%n.d.n.d.
31564432rWGSInfants; disease of unknown etiology; within 96 hours of admission9419%24%10%
rWES9520%20%18%
urWGS2446%63%25%
Baby BearurWGSMediCal Infants; <1 week of admission17843%31%n.d.
Baby ManateeurWGSInpatient children; 90% in ICUs5040%38%n.d.

Timely Dissemination

When we return genetic test results, we make experts available to assist the doctors caring for a child to find the most up to date information on the disorder.

RCIGM Related Publications

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing
Wigby K, Hammer M, Tokita M, Patel P, Jones MC, Larson A, Bartolomei FV, Dykzeul N, Slavotinek A, Yip T, Bandres-Ciga S, Simpson BN, Suhrie K, Shankar S, Veith R, Bragg J, Powell C, Kingsmore SF, Dimmock D, Maron J, Davis J, Del Campo M.

Am J Med Genet A. 2023 Jan 18. doi: 10.1002/ajmg.a.63097. Online ahead of print.

ABSTRACT

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.

PMID:36651673 DOI:10.1002/ajmg.a.63097

Breaking Barriers to Rapid Whole Genome Sequencing in Pediatrics: Michigan’s Project Baby Deer
Bupp CP, Ames EG, Arenchild MK, Caylor S, Dimmock DP, Fakhoury JD, Karna P, Lehman A, Meghea CI, Misra V, Nolan DA, O’Shea J, Sharangpani A, Franck LS, Scheurer-Monaghan A.

Children. 2023; 10(1):106. https://doi.org/10.3390/children10010106

ABSTRACT
The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan’s Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project’s impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95–214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.
Rapid Whole Genome Sequencing in Critically Ill Neonates Enables Precision Medicine Pipeline
Beaman M, Fisher K, McDonald M, Tan QKG, Jackson D, Cocanougher BT, Landstrom AP, Hobbs CA, Cotten M, Cohen JL.

J Pers Med. 2022 Nov 18;12(11):1924. doi: 10.3390/jpm12111924.

ABSTRACT

Rapid genome sequencing in critically ill infants is increasingly identified as a crucial test for providing targeted and informed patient care. We report the outcomes of a pilot study wherein eight critically ill neonates received rapid whole genome sequencing with parental samples in an effort to establish a prompt diagnosis. Our pilot study resulted in a 37.5% diagnostic rate by whole genome sequencing alone and an overall 50% diagnostic rate for the cohort. We describe how the diagnoses led to identification of additional affected relatives and a change in management, the limitations of rapid genome sequencing, and some of the challenges with sample collection. Alongside this pilot study, our site simultaneously established a research protocol pipeline that will allow us to conduct research-based genomic testing in the cases for which a diagnosis was not reached by rapid genome sequencing or other available clinical testing. Here we describe the benefits, limitations, challenges, and potential for rapid whole genome sequencing to be incorporated into routine clinical evaluation in the neonatal period.

PMID:36422100 DOI:10.3390/jpm12111924

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases
Mallory J. Owen, Sebastien Lefebvre, Christian Hansen, Chris M. Kunard, David P. Dimmock, Laurie D. Smith, Gunter Scharer, Rebecca Mardach, Mary J. Willis, Annette Feigenbaum, Anna-Kaisa Niemi, Yan Ding, Luca Van Der Kraan, Katarzyna Ellsworth, Lucia Guidugli, Bryan R. Lajoie, Timothy K. McPhail, Shyamal S. Mehtalia, Kevin K. Chau, Yong H. Kwon, Zhanyang Zhu, Sergey Batalov, Shimul Chowdhury, Seema Rego, James Perry, Mark Speziale, Mark Nespeca, Meredith S. Wright, Martin G. Reese, Francisco M. De La Vega, Joe Azure, Erwin Frise, Charlene Son Rigby, Sandy White, Charlotte A. Hobbs, Sheldon Gilmer, Gail Knight, Albert Oriol, Jerica Lenberg, Shareef A. Nahas, Kate Perofsky, Kyu Kim, Jeanne Carroll, Nicole G. Coufal, Erica Sanford, Kristen Wigby, Jacqueline Weir, Vicki S. Thomson, Louise Fraser, Seka S. Lazare, Yoon H. Shin, Haiying Grunenwald, Richard Lee, David Jones, Duke Tran, Andrew Gross, Patrick Daigle, Anne Case, Marisa Lue, James A. Richardson, John Reynders, Thomas Defay, Kevin P. Hall, Narayanan Veeraraghavan & Stephen F. Kingsmore

Nat Commun. 2022 Jul 26;13(1):4057. doi: 10.1038/s41467-022-31446-6.

While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports (https://gtrx.radygenomiclab.com). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.

PMID:35882841 | DOI:10.1038/s41467-022-31446-6

Ultra Rapid Whole Genome Sequencing: A Paradigm Shift in the Pre-Transplant Evaluation of Neonatal Acute Liver Failure
Thompson WS, Greenmyer JR, Lanpher BC, Brumbaugh JE, Bendel-Stenzel EM, Dimmock DP, Hobbs CA, Ibrahim SH, Hildreth AN.

Liver Transpl. 2022 Jul 21. doi: 10.1002/lt.26547. Online ahead of print.

NO ABSTRACT

PMID:35861277 | DOI:10.1002/lt.26547

Better and Faster is Cheaper
Sanford Kobayashi EF, Dimmock DP. 

Hum Mutat. 2022 Jun 20. doi: 10.1002/humu.24422. Online ahead of print.

ABSTRACT

The rapid pace of advancement in genomic sequencing technology has recently reached a new milestone, with a record-setting time to molecular diagnosis of a mere eight hours. The catalyst behind this achievement is the accumulation of evidence indicating that quicker results more often make an impact on patient care and lead to healthcare cost savings. Herein, we review the diagnostic and clinical utility of rapid whole genome and rapid whole exome sequencing, the associated reduction in healthcare costs, and the relationship between these outcome measures and time-to-diagnosis. This article is protected by copyright. All rights reserved.

PMID:35723630 | DOI:10.1002/humu.24422

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Robert Wechler-Reva

PHD, Neuro-Oncology Program Director

Noted scientist Robert Wechsler-Reya, PhD, is also a professor and researcher at the Sanford Burnham Prebys Medical Discovery Institute (SBP) where he is focused on investigating the genes and nervous system signaling pathways that contribute to medulloblastoma, the most common malignant brain tumor in children.

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