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
March 14, 2023
RPM for NICU and PICU
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
February 14, 2023
Newborn ScreeningRPM for NICU and PICUrWGS
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
January 31, 2023
RPM for NICU and PICUrWGSrWGS Efficacy
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
January 18, 2023
Rare DiseaseRPM for NICU and PICU
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.
January 4, 2023
RPM for NICU and PICUrWGSrWGS Efficacy
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
November 18, 2022
RPM for NICU and PICUrWGSrWGS Efficacy
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
July 21, 2022
RPM for NICU and PICUrWGS
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
June 20, 2022
RPM for NICU and PICUrWGSrWGS Efficacy
The Role of Genome Sequencing in Neonatal Intensive Care Units
Kingsmore SF, Cole FS.
Annu Rev Genomics Hum Genet. 2022 Jun 8. doi: 10.1146/annurev-genom-120921-103442. Online ahead of print.
ABSTRACT
Genetic diseases disrupt the functionality of an infant’s genome during fetal-neonatal adaptation and represent a leading cause of neonatal and infant mortality in the United States. Due to disease acuity, gene locus and allelic heterogeneity, and overlapping and diverse clinical phenotypes, diagnostic genome sequencing in neonatal intensive care units has required the development of methods to shorten turnaround times and improve genomic interpretation. From 2012 to 2021, 31 clinical studies documented the diagnostic and clinical utility of first-tier rapid or ultrarapid whole-genome sequencing through cost-effective identification of pathogenic genomic variants that change medical management, suggest new therapeutic strategies, and refine prognoses. Genomic diagnosis also permits prediction of reproductive recurrence risk for parents and surviving probands. Using implementation science and quality improvement, deployment of a genomic learning healthcare system will contribute to a reduction of neonatal and infant mortality through the integration of genome sequencing into best-practice neonatal intensive care. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PMID:
35676073 | DOI:
10.1146/annurev-genom-120921-103442
June 8, 2022
Infant MortalityRPM for NICU and PICUrWGSrWGS Efficacy