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

Rapid Whole Genome Sequencing for Diagnosis of Single Locus Genetic Diseases in Critically Ill Children
Owen MJ, Batalov S, Ellsworth KA, Wright M, Breeding S, Hugh K, Kingsmore SF, Ding Y.

Methods Mol Biol. 2023;2621:217-239. doi: 10.1007/978-1-0716-2950-5_12.

ABSTRACT

Upon admission to intensive care units (ICU), the differential diagnosis of almost all infants with diseases of unclear etiology includes single locus genetic diseases. Rapid whole genome sequencing (rWGS), including sample preparation, short-read sequencing-by-synthesis, informatics pipelining, and semiautomated interpretation, can now identify nucleotide and structural variants associated with most genetic diseases with robust analytic and diagnostic performance in as little as 13.5 h. Early diagnosis of genetic diseases transforms medical and surgical management of infants in ICUs, minimizing both the duration of empiric treatment and the delay to start of specific treatment. Both positive and negative rWGS tests have clinical utility and can improve outcomes. Since first described 10 years ago, rWGS has evolved considerably. Here we describe our current methods for routine diagnostic testing for genetic diseases by rWGS in as little as 18 h.

PMID:37041447 DOI:10.1007/978-1-0716-2950-5_12

Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning
Peterson B, Hernandez EJ, Hobbs C, Malone Jenkins S, Moore B, Rosales E, Zoucha S, Sanford E, Bainbridge MN, Frise E, Oriol A, Brunelli L, Kingsmore SF, Yandell M.

Genome Med. 2023 Mar 16;15(1):18. doi: 10.1186/s13073-023-01166-7.

ABSTRACT

BACKGROUND: Rapidly and efficiently identifying critically ill infants for whole genome sequencing (WGS) is a costly and challenging task currently performed by scarce, highly trained experts and is a major bottleneck for application of WGS in the NICU. There is a dire need for automated means to prioritize patients for WGS.

METHODS: Institutional databases of electronic health records (EHRs) are logical starting points for identifying patients with undiagnosed Mendelian diseases. We have developed automated means to prioritize patients for rapid and whole genome sequencing (rWGS and WGS) directly from clinical notes. Our approach combines a clinical natural language processing (CNLP) workflow with a machine learning-based prioritization tool named Mendelian Phenotype Search Engine (MPSE).

RESULTS: MPSE accurately and robustly identified NICU patients selected for WGS by clinical experts from Rady Children’s Hospital in San Diego (AUC 0.86) and the University of Utah (AUC 0.85). In addition to effectively identifying patients for WGS, MPSE scores also strongly prioritize diagnostic cases over non-diagnostic cases, with projected diagnostic yields exceeding 50% throughout the first and second quartiles of score-ranked patients.

CONCLUSIONS: Our results indicate that an automated pipeline for selecting acutely ill infants in neonatal intensive care units (NICU) for WGS can meet or exceed diagnostic yields obtained through current selection procedures, which require time-consuming manual review of clinical notes and histories by specialized personnel.

PMID:36927505 DOI:10.1186/s13073-023-01166-7

Genomic sequencing has a high diagnostic yield in children with congenital anomalies of the heart and urinary system
Allred ET, Perens EA, Coufal NG, Sanford Kobayashi E, Kingsmore SF, Dimmock DP. 

Front Pediatr. 2023 Mar 14;11:1157630. doi: 10.3389/fped.2023.1157630. eCollection 2023.

ABSTRACT

BACKGROUND: Congenital heart defects (CHD) and congenital anomalies of the kidney and urinary tract (CAKUT) account for significant morbidity and mortality in childhood. Dozens of monogenic causes of anomalies in each organ system have been identified. However, even though 30% of CHD patients also have a CAKUT and both organs arise from the lateral mesoderm, there is sparse overlap of the genes implicated in the congenital anomalies for these organ systems. We sought to determine whether patients with both CAKUT and CHD have a monogenic etiology, with the long-term goal of guiding future diagnostic work up and improving outcomes.

METHODS: Retrospective review of electronic medical records (EMR), identifying patients admitted to Rady Children’s Hospital between January 2015 and July 2020 with both CAKUT and CHD who underwent either whole exome sequencing (WES) or whole genome sequencing (WGS). Data collected included demographics, presenting phenotype, genetic results, and mother’s pregnancy history. WGS data was reanalyzed with a specific focus on the CAKUT and CHD phenotype. Genetic results were reviewed to identify causative, candidate, and novel genes for the CAKUT and CHD phenotype. Associated additional structural malformations were identified and categorized.

RESULTS: Thirty-two patients were identified. Eight patients had causative variants for the CAKUT/CHD phenotype, three patients had candidate variants, and three patients had potential novel variants. Five patients had variants in genes not associated with the CAKUT/CHD phenotype, and 13 patients had no variant identified. Of these, eight patients were identified as having possible alternative causes for their CHD/CAKUT phenotype. Eighty-eight percent of all CAKUT/CHD patients had at least one additional organ system with a structural malformation.

CONCLUSIONS: Overall, our study demonstrated a high rate of monogenic etiologies in hospitalized patients with both CHD and CAKUT, with a diagnostic rate of 44%. Thus, physicians should have a high suspicion for genetic disease in this population. Together, these data provide valuable information on how to approach acutely ill patients with CAKUT and CHD, including guiding diagnostic work up for associated phenotypes, as well as novel insights into the genetics of CAKUT and CHD overlap syndromes in hospitalized children.

PMID:36999085 DOI:10.3389/fped.2023.1157630

Artificial Intelligence in the Genetic Diagnosis of Rare Disease
James KN, Phadke S, Wong TC, Chowdhury S.

Clin Lab Med. 2023 Mar;43(1):127-143. doi: 10.1016/j.cll.2022.09.023.

Part of special issue: Artificial Intelligence in the Clinical Laboratory: Current Practice and Emerging Opportunities

PMID:36764805 DOI:10.1016/j.cll.2022.09.023

Scalable, high quality, whole genome sequencing from archived, newborn, dried blood spots
Ding Y, Owen M, Le J, Batalov S, Chau K, Kwon YH, Van Der Kraan L, Bezares-Orin Z, Zhu Z, Veeraraghavan N, Nahas S, Bainbridge M, Gleeson J, Baer RJ, Bandoli G, Chambers C, Kingsmore SF. 

NPJ Genom Med. 2023 Feb 14;8(1):5. doi: 10.1038/s41525-023-00349-w.

ABSTRACT

Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies.

PMID:36788231 DOI:10.1038/s41525-023-00349-w

25: A Multicenter Cohort Analysis of Rapid Genome Sequencing in the PICU
Rodriguez, Katherine; Kobayashi, Erica Sanford; VanDongen-Trimmer, Heather; Salz, Lisa; Foley, Jennifer; Whalen, Drewann; Oluchukwu, Okonkwo; Liu, Kuang Chuen; Burton, Jennifer; Syngal, Prachi; Kingsmore, Stephen; Coufal, Nicole.

Critical Care Medicine 51(1):p 13, January 2023.

Genetic disorders contribute significantly to morbidity and mortality in pediatric critical care. Diagnostic rapid whole genome sequencing (rWGS) has dramatically impacted care in neonatal intensive care units (ICU). There remains a population of undiagnosed patients with rare genetic diseases who present critically ill to the pediatric ICU (PICU) and the application of rWGS in this setting is not yet fully described. This study evaluated the clinical utility of rWGS in the PICU.

DOI: 10.1097/01.ccm.0000905976.97417.e4

Rapid Precision Medicine In the News

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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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