Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics
Hopkins CE, Brock T, Caulfield TR, Bainbridge M.
Mol Aspects Med. 2022 Nov 18:101153. doi: 10.1016/j.mam.2022.101153. Online ahead of print.
ABSTRACT
Precision medicine strives for highly individualized treatments for disease under the notion that each individual’s unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In the realm of rare disorders, genetic predisposition is often the predominant mechanism driving disease presentation. For such, mostly, monogenic disorders, a causal gene to phenotype association is likely. As a result, it becomes important to query the patient’s genome for the presence of pathogenic variations that are likely to cause the disease. Determining whether a variant is pathogenic or not is critical to these analyses and can be challenging, as many disease-causing variants are novel and, ergo, have no available functional data to help categorize them. This problem is exacerbated by the need for rapid evaluation of pathogenicity, since many genetic diseases present in young children who will experience increased morbidity and mortality without rapid diagnosis and therapeutics. Here, we discuss the utility of animal models, with a focus mainly on C. elegans, as a contrast to tissue culture and in silico approaches, with emphasis on how these systems are used in determining pathogenicity of variants with uncertain significance and then used to screen for novel therapeutics.
PMID:
36411139 DOI:
10.1016/j.mam.2022.101153
November 18, 2022
rWGS
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
Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding
Mark PR, Murray SA, Yang T, Eby A, Lai A, Lu D, Zieba J, Rajasekaran S, VanSickle EA, Rossetti LZ, Guidugli L, Watkins K, Wright MS, Bupp CP, Prokop JW.
Cold Spring Harb Mol Case Stud. 2022 Oct 28;8(6):a006169. doi: 10.1101/mcs.a006169. Print 2022 Oct.
ABSTRACT
We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in LRP1, in which segregation analysis helped dismiss additional variants of interest. LRP1 analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells.
PMID:
36307211 DOI:
10.1101/mcs.a006169
October 28, 2022
rWGS
Approaches to long-read sequencing in a clinical setting to improve diagnostic rate
Sanford Kobayashi E, Batalov S, Wenger AM, Lambert C, Dhillon H, Hall RJ, Baybayan P, Ding Y, Rego S, Wigby K, Friedman J, Hobbs C, Bainbridge MN.
Sci Rep. 2022 Oct 9;12(1):16945. doi: 10.1038/s41598-022-20113-x.
ABSTRACT
Over the past decade, advances in genetic testing, particularly the advent of next-generation sequencing, have led to a paradigm shift in the diagnosis of molecular diseases and disorders. Despite our present collective ability to interrogate more than 90% of the human genome, portions of the genome have eluded us, resulting in stagnation of diagnostic yield with existing methodologies. Here we show how application of a new technology, long-read sequencing, has the potential to improve molecular diagnostic rates. Whole genome sequencing by long reads was able to cover 98% of next-generation sequencing dead zones, which are areas of the genome that are not interpretable by conventional industry-standard short-read sequencing. Through the ability of long-read sequencing to unambiguously call variants in these regions, we discovered an immunodeficiency due to a variant in IKBKG in a subject who had previously received a negative genome sequencing result. Additionally, we demonstrate the ability of long-read sequencing to detect small variants on par with short-read sequencing, its superior performance in identifying structural variants, and thirdly, its capacity to determine genomic methylation defects in native DNA. Though the latter technical abilities have been demonstrated, we demonstrate the clinical application of this technology to successfully identify multiple types of variants using a single test.
PMID:
36210382 DOI:
10.1038/s41598-022-20113-x
October 9, 2022
rWGS
A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases
Kingsmore SF, Smith LD, Kunard CM, Bainbridge M, Batalov S, Benson W, Blincow E, Caylor S, Chambers C, Del Angel G, Dimmock DP, Ding Y, Ellsworth K, Feigenbaum A, Frise E, Green RC, Guidugli L, Hall KP, Hansen C, Hobbs CA, Kahn SD, Kiel M, Van Der Kraan L, Krilow C, Kwon YH, Madhavrao L, Le J, Lefebvre S, Mardach R, Mowrey WR, Oh D, Owen MJ, Powley G, Scharer G, Shelnutt S, Tokita M, Mehtalia SS, Oriol A, Papadopoulos S, Perry J, Rosales E, Sanford E, Schwartz S, Tran D, Reese MG, Wright M, Veeraraghavan N, Wigby K, Willis MJ, Wolen AR, Defay T.
Am J Hum Genet. 2022 Aug 18:S0002-9297(22)00355-X. doi: 10.1016/j.ajhg.2022.08.003. Online ahead of print.
ABSTRACT
Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.
PMID:
36007526 | DOI:
10.1016/j.ajhg.2022.08.003
August 24, 2022
Newborn ScreeningrWGS
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
July 26, 2022
Newborn ScreeningRare DiseaseRPM for NICU and PICUrWGS
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
Neonatal familial hemophagocytic lymphohistiocytosis diagnosed with ultrarapid whole-genome sequencing
Greenmyer JR, Thompson WS, Mavis S, Hassan S, Weckwerth J, Hobbs C, James K, Nahas S, Galardy P, Collura C.
Pediatr Blood Cancer. 2022 Jul 7:e29871. doi: 10.1002/pbc.29871. Online ahead of print.
NO ABSTRACT
PMID:
35796407 | DOI:
10.1002/pbc.29871
July 7, 2022
rWGS
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
