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 multiple 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

Genome sequencing detects a wide range of clinically relevant copy number variants and other genomic alterations
James KN, Chowdhury S, Ding Y, Batalov S, Watkins K, Kwon YH, Van Der Kraan L, Ellsworth K, Kingsmore SF, Guidugli L. 

Genet Med. 2023 Oct 20:101006. doi: 10.1016/j.gim.2023.101006. Online ahead of print.

ABSTRACT

PURPOSE: Copy number variants (CNVs) and other non-SNV/indel variant types contribute an important proportion of diagnoses in individuals with suspected genetic disease. This study describes the range of such variants detected by genome sequencing (GS).

METHODS: For a pediatric cohort of 1032 participants undergoing clinical GS, we characterize the CNVs and other non-SNV/indel variant types that were reported, including aneuploidies, mobile element insertions, and uniparental disomies, and we describe the bioinformatic pipeline used to detect these variants.

RESULTS: Together, these genetic alterations accounted for 15.8% of reported variants. Notably, 67.9% of these were deletions, 32.9% of which overlapped a single gene, and many deletions were reported together with a second variant in the same gene in cases of recessive disease. A retrospective medical record review in a subset of this cohort revealed that up to six additional genetic tests were ordered in 68% (26/38) of cases, some of which failed to report the CNVs/rare variants reported on GS.

CONCLUSION: GS detected a broad range of reported variant types, including CNVs ranging in size from 1 Kb to 46 Mb.

PMID:37869996 DOI:10.1016/j.gim.2023.101006

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Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder
Maron JL, Kingsmore S, Gelb BD, Vockley J, Wigby K, Bragg J, Stroustrup A, Poindexter B, Suhrie K, Kim J, Diacovo T, Powell CM, Trembath A, Guidugli L, Ellsworth KA, Reed D, Kurfiss A, Breeze JL, Trinquart L, Davis JM

JAMA. 2023 Jul 11;330(2):161-169. doi: 10.1001/jama.2023.9350.

ABSTRACT

IMPORTANCE: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results.

OBJECTIVE: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.

DESIGN, SETTING, AND PARTICIPANTS: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021.

EXPOSURE: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient’s phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform.

MAIN OUTCOMES AND MEASURES: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care).

RESULTS: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis.

CONCLUSIONS AND RELEVANCE: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.

PMID:37432431 DOI:10.1001/jama.2023.9350

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Assessing Diversity in Newborn Genomic Sequencing Research Recruitment: Race/Ethnicity and Primary Spoken Language Variation in Eligibility, Enrollment, and Reasons for Declining
Cakici JA, Dimmock D, Caylor S, Gaughran M, Clarke C, Triplett C, Clark MM, Kingsmore SF, Bloss CS.

Clin Ther. 2023 Jul 8:S0149-2918(23)00220-5. doi: 10.1016/j.clinthera.2023.06.014. Online ahead of print.

ABSTRACT

PURPOSE: Diagnostic genomic research has the potential to directly benefit participants. This study sought to identify barriers to equitable enrollment of acutely ill newborns into a diagnostic genomic sequencing research study.

METHODS: We reviewed the 16-month recruitment process of a diagnostic genomic research study enrolling newborns admitted to the neonatal intensive care unit at a regional pediatric hospital that primarily serves English- and Spanish-speaking families. Differences in eligibility, enrollment, and reasons for not enrolling were examined as functions of race/ethnicity and primary spoken language.

FINDINGS: Of the 1248 newborns admitted to the neonatal intensive care unit, 46% (n = 580) were eligible, and 17% (n = 213) were enrolled. Of the 16 languages represented among the newborns’ families, 4 (25%) had translated consent documents. Speaking a language other than English or Spanish increased a newborn’s likelihood of being ineligible by 5.9 times (P < 0.001) after controlling for race/ethnicity. The main reason for ineligibility was documented as the clinical team declined having their patient recruited (41% [51 of 125]). This reason significantly affected families who spoke languages other than English or Spanish and was able to be remediated with training of the research staff. Stress (20% [18 of 90]) and the study intervention(s) (20% [18 of 90]) were the main reasons given for not enrolling.

IMPLICATIONS: This analysis of eligibility, enrollment, and reasons for not enrolling in a diagnostic genomic research study found that recruitment generally did not differ as a function of a newborn’s race/ethnicity. However, differences were observed depending on the parent’s primary spoken language. Regular monitoring and training can improve equitable enrollment into diagnostic genomic research. There are also opportunities at the federal level to improve access to those with limited English proficiency and thus decrease disparities in representation in research participation.

PMID:37429778 DOI:10.1016/j.clinthera.2023.06.014

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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

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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

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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

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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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