Scientific Publications

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222 Results

2022

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 13, 4057 (2022). 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. DOI:10.1038/s41467-022-31446-6

July 26, 2022
Rare 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

Wastewater sequencing reveals early cryptic SARS-CoV-2 variant transmission

Karthikeyan S, Levy JI, De Hoff P, Humphrey G, Birmingham A, Jepsen K, Farmer S, Tubb HM, Valles T, Tribelhorn CE, Tsai R, Aigner S, Sathe S, Moshiri N, Henson B, Mark AM, Hakim A, Baer NA, Barber T, Belda-Ferre P, Chacón M, Cheung W, Cresini ES, Eisner ER, Lastrella AL, Lawrence ES, Marotz CA, Ngo TT, Ostrander T, Plascencia A, Salido RA, Seaver P, Smoot EW, McDonald D, Neuhard RM, Scioscia AL, Satterlund AM, Simmons EH, Abelman DB, Brenner D, Bruner JC, Buckley A, Ellison M, Gattas J, Gonias SL, Hale M, Hawkins F, Ikeda L, Jhaveri H, Johnson T, Kellen V, Kremer B, Matthews G, McLawhon RW, Ouillet P, Park D, Pradenas A, Reed S, Riggs L, Sanders A, Sollenberger B, Song A, White B, Winbush T, Aceves CM, Anderson C, Gangavarapu K, Hufbauer E, Kurzban E, Lee J, Matteson NL, Parker E, Perkins SA, Ramesh KS, Robles-Sikisaka R, Schwab MA, Spencer E, Wohl S, Nicholson L, Mchardy IH, Dimmock DP, Hobbs CA, Bakhtar O, Harding A, Mendoza A, Bolze A, Becker D, Cirulli ET, Isaksson M, Schiabor Barrett KM, Washington NL, Malone JD, Schafer AM, Gurfield N, Stous S, Fielding-Miller R, Garfein RS, Gaines T, Anderson C, Martin NK, Schooley R, Austin B, MacCannell DR, Kingsmore SF, Lee W, Shah S, McDonald E, Yu AT, Zeller M, Fisch KM, Longhurst C, Maysent P, Pride D, Khosla PK, Laurent LC, Yeo GW, Andersen KG, Knight R.

Nature. 2022 Jul 7. doi: 10.1038/s41586-022-05049-6. Online ahead of print. ABSTRACT As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing/sequencing capacity, which can also introduce biases1-3. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing4,5. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here, we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We develop and deploy improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detect emerging variants of concern up to 14 days earlier in wastewater samples, and identify multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission. PMID:35798029 | DOI:10.1038/s41586-022-05049-6

July 7, 2022

Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission

Breuss MW, Yang X, Stanley V, McEvoy-Venneri J, Xu X, Morales AJ, Gleeson JG. 

Elife. 2022 Jul 5;11:e78459. doi: 10.7554/eLife.78459. ABSTRACT BACKGROUND: De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring. METHODS: As a cohort study, in three independent couples undergoing in vitro fertilization, we first identified male gonadal mosaicism through deep whole genome sequencing. We then confirmed variants and assessed their transmission to preimplantation blastocysts (32 total) through targeted ultra-deep genotyping. RESULTS: Across 55 gonadal mosaic variants, 15 were transmitted to blastocysts for a total of 19 transmission events. This represented an overall predictable but slight undertransmission based upon the measured mutational abundance in sperm. We replicated this conclusion in an independent, previously published family-based cohort. CONCLUSIONS: Unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations. This-in turn-could help to reduce their impact on miscarriages and pediatric disease. FUNDING: No external funding was received for this work. PMID:35787314 | DOI:10.7554/eLife.78459

July 5, 2022
Neurogenomics

Random Field Modeling of Multi-trait Multi-locus Association for Detecting Methylation Quantitative Trait Loci

Lyu C, Huang M, Liu N, Chen Z, Lupo PJ, Tycko B, Witte JS, Hobbs CA, Li M.

Bioinformatics. 2022 Jul 4:btac443. doi: 10.1093/bioinformatics/btac443. Online ahead of print. ABSTRACT MOTIVATION: CpG sites within the same genomic region often share similar methylation patterns and tend to be co-regulated by multiple genetic variants that may interact with one another. RESULTS: We propose a multi-trait methylation random field (multi-MRF) method to evaluate the joint association between a set of CpG sites and a set of genetic variants. The proposed method has several advantages. First, it is a multi-trait method that allows flexible correlation structures between neighboring CpG sites (e.g., distance-based correlation). Second, it is also a multi-locus method that integrates the effect of multiple common and rare genetic variants. Third, it models the methylation traits with a beta distribution to characterize their bimodal and interval properties. Through simulations, we demonstrated that the proposed method had improved power over some existing methods under various disease scenarios. We further illustrated the proposed method via an application to a study of congenital heart defects (CHD) with 83 cardiac tissue samples. Our results suggested that gene BACE2, a mQTL candidate, colocalized with expression QTLs in artery tibial and harbored genetic variants with nominal significant associations in two genome-wide association studies of CHD. AVAILABILITY: https://github.com/chenlyu2656/Multi-MRF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID:35781319 | DOI:10.1093/bioinformatics/btac443

July 4, 2022

Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders

Di Donato N, Guerrini R, Billington CJ, Barkovich AJ, Dinkel P, Freri E, Heide M, Gershon ES, Gertler TS, Hopkin RJ, Jacob S, Keedy SK, Kooshavar D, Lockhart PJ, Lohmann DR, Mahmoud IG, Parrini E, Schrock E, Severi G, Timms AE, Webster RI, Willis MJH, Zaki MS, Gleeson JG, Leventer RJ, Dobyns WB.

Brain. 2022 Jun 30:awac164. doi: 10.1093/brain/awac164. Online ahead of print. ABSTRACT Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a ‘reeling’ gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging. PMID:35769015 | DOI:10.1093/brain/awac164

June 30, 2022
Neurogenomics

Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome (NODRS)

Bainbridge MN, Mazumder A, Ogasawara D, Abou Jamra R, Bernard G, Bertini E, Burglen L, Cope H, Crawford A, Derksen A, Dure L, Gantz E, Koch-Hogrebe M, Hurst ACE, Mahida S, Marshall P, Micalizzi A, Novelli A, Peng H, Rodriguez D, Robbins SL, Rutledge SL, Scalise R, Schließke S, Shashi V, Srivastava S, Thiffault I, Topol S; Undiagnosed Disease Network, Qebibo L, Wieczorek D, Cravatt B, Haricharan S, Torkamani A, Friedman J. 

Brain. 2022 Jun 23:awac223. doi: 10.1093/brain/awac223. Online ahead of print. ABSTRACT The endocannabinoid system is a highly conserved and ubiquitous signaling pathway with broad ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia, and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNAseq showed clear expression of the truncated transcript and no differences were found between mutant and wild type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique pediatric syndrome. Because enzymatic activity was preserved, the observed mis-localization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues. PMID:35737950 | DOI:10.1093/brain/awac223

June 23, 2022
Neurogenomics

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 PICUrWGS

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 PICUrWGS

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