Scientific Publications

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Duis blandit elit metus, mattis consectetur eros fermentum id. Cras lorem purus, finibus vel aliquam ac, porta in libero. Cras lorem purus, finibus vel aliquam ac, porta in libero.

  • Results Per Page

324 Results


Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023

Rodriguez KM, Vaught J, Salz L, Foley J, Boulil Z, Van Dongen-Trimmer HM, Whalen D, Oluchukwu O, Liu KC, Burton J, Syngal P, Vargas-Shiraishi O, Kingsmore SF, Sanford Kobayashi E, Coufal NG.

Pediatr Crit Care Med. 2024 Apr 26. doi: 10.1097/PCC.0000000000003522. Online ahead of print. ABSTRACT OBJECTIVES: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions. DESIGN: Ambidirectional multisite cohort study. SETTING: Four tertiary children’s hospitals. PATIENTS: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication (p < 0.0001) and contributed to a decision to consult palliative care (p < 0.02). CONCLUSIONS: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management. PMID:38668387 | DOI:10.1097/PCC.0000000000003522

April 26, 2024

Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action

Jobanputra V, Schroeder B, Rehm HL, Shen W, Spiteri E, Nakouzi G, Taylor S, Marshall CR, Meng L, Kingsmore SF, Ellsworth K, Ashley E, Taft RJ; Medical Genome Initiative.

NPJ Genom Med. 2024 Mar 27;9(1):23. doi: 10.1038/s41525-024-00410-2. NO ABSTRACT PMID:38538605 | DOI:10.1038/s41525-024-00410-2

March 27, 2024
Rare Disease

The contribution of de novo coding mutations to meningomyelocele

Yoo-Jin Ha, Isaac Tang, Ashna Nisal, Ishani Jhamb, Cassidy Wallace, Sarah Schroeder, Chanjae Lee, Keng loi Vong, Naomi Meave, Fiza Jiwani, Chelsea Barrows, Sangmoon Lee, Nan Jiang, Arzoo Patel, Francisco A. Blanco, Seyoung Yu, Hui Su Jeong, Isaac Plutzer, Michael B. Major, Béatrice Benoit, Christian Poüs, Caleb Heffner, Zoha Kibar, Gyang Markus Bot, Hope Northrup, Kit Sing Au, Madison Strain, Allison Ashley-Koch, Richard H. Finnell, Joan T. Le, Hal Meltzer, Camila Araujo, Helio R. Machado, Roger E. Stevenson, Anna Yurrita, Sara Mumtaz, Osvaldo M. Mutchinick, José Ramón Medina-Bereciartu, Friedhelm Hildebrandt, Gia Melikishvili, Rony Marwan, Valeria Capra, Mahmoud M. Noureldeen, Aida M.S. Salem, Mahmoud Y. Issa, Maha S. Zaki, Ji Eun Lee, Anna Alkelai, Alan R. Shuldiner, Stephen F. Kingsmore, Stephen A. Murray, Heon Yung Gee, W. Todd Miller, Kimberley F. Tolias, John B. Wallingford, Spina Bifida Sequencing Consortium, Sangwoo Kim, Joseph G. Gleeson

medRxiv, March 2, 2024. ABSTRACT Meningomyelocele (MM) is considered a genetically complex disease resulting from failure of neural tube closure (NTD). Patients display neuromotor disability and frequent hydrocephalus requiring ventricular shunting. A few proposed genes contribute to disease susceptibility, but most risk remains unexplained. We postulated that de novo mutations (DNMs) under purifying selection contribute to MM risk. Here we recruited a cohort of 851 MM trios requiring shunting at birth, compared with 732 control trios, and found that de novo likely gene disrupting or damaging missense mutations occur in approximately 22.3% of subjects, 28% of which are estimated to contribute to disease risk. The 187 genes with damaging DNMs collectively define networks including actin cytoskeleton and microtubule-based processes, axon guidance, and histone modification. Gene validation demonstrates partial or complete loss of function, impaired signaling and defective neural tube closure in Xenopus embryos. Our results suggest DNMs make key contributions to MM risk, and highlight critical pathways required for neural tube closure in human embryogenesis. DOI:10.1101/2024.02.28.24303390

March 2, 2024

Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review

Kingsmore SF, Nofsinger R, Ellsworth K.

NPJ Genom Med. 2024 Feb 27;9(1):17. doi: 10.1038/s41525-024-00404-0. ABSTRACT Single locus (Mendelian) diseases are a leading cause of childhood hospitalization, intensive care unit (ICU) admission, mortality, and healthcare cost. Rapid genome sequencing (RGS), ultra-rapid genome sequencing (URGS), and rapid exome sequencing (RES) are diagnostic tests for genetic diseases for ICU patients. In 44 studies of children in ICUs with diseases of unknown etiology, 37% received a genetic diagnosis, 26% had consequent changes in management, and net healthcare costs were reduced by $14,265 per child tested by URGS, RGS, or RES. URGS outperformed RGS and RES with faster time to diagnosis, and higher rate of diagnosis and clinical utility. Diagnostic and clinical outcomes will improve as methods evolve, costs decrease, and testing is implemented within precision medicine delivery systems attuned to ICU needs. URGS, RGS, and RES are currently performed in <5% of the ~200,000 children likely to benefit annually due to lack of payor coverage, inadequate reimbursement, hospital policies, hospitalist unfamiliarity, under-recognition of possible genetic diseases, and current formatting as tests rather than as a rapid precision medicine delivery system. The gap between actual and optimal outcomes in children in ICUs is currently increasing since expanded use of URGS, RGS, and RES lags growth in those likely to benefit through new therapies. There is sufficient evidence to conclude that URGS, RGS, or RES should be considered in all children with diseases of uncertain etiology at ICU admission. Minimally, diagnostic URGS, RGS, or RES should be ordered early during admissions of critically ill infants and children with suspected genetic diseases. PMID:38413639 | DOI:10.1038/s41525-024-00404-0

February 27, 2024
RPM for NICU and PICUrWGSrWGS Efficacy

Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders

Wigby KM, Brockman D, Costain G, Hale C, Taylor SL, Belmont J, Bick D, Dimmock D, Fernbach S, Greally J, Jobanputra V, Kulkarni S, Spiteri E, Taft RJ.

NPJ Genom Med. 2024 Feb 26;9(1):15. doi: 10.1038/s41525-024-00396-x. ABSTRACT Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations. PMID:38409289 | DOI:10.1038/s41525-024-00396-x

February 26, 2024
Rare DiseaseRPM for NICU and PICU

Multi-center implementation of rapid whole genome sequencing provides additional evidence of its utility in the pediatric inpatient setting

Thompson L, Larson A, Salz L, Veith R, Tsai JP, Jayakar A, Chapman R, Gupta A, Kingsmore SF, Dimmock D, Bedrick A, Galindo MK, Casas K, Mohamed M, Straight L, Khan MA, Salyakina D.

Front Pediatr. 2024 Feb 19;12:1349519. doi: 10.3389/fped.2024.1349519. eCollection 2024. ABSTRACT OBJECTIVE: Multi-center implementation of rapid whole genome sequencing with assessment of the clinical utility of rapid whole genome sequencing (rWGS), including positive, negative and uncertain results, in admitted infants with a suspected genetic disease. STUDY DESIGN: rWGS tests were ordered at eight hospitals between November 2017 and April 2020. Investigators completed a survey of demographic data, Human Phenotype Ontology (HPO) terms, test results and impacts of results on clinical care. RESULTS: A total of 188 patients, on general hospital floors and intensive care unit (ICU) settings, underwent rWGS testing. Racial and ethnic characteristics of the tested infants were broadly representative of births in the country at large. 35% of infants received a diagnostic result in a median of 6 days. The most common HPO terms for tested infants indicated an abnormality of the nervous system, followed by the cardiovascular system, the digestive system, the respiratory system and the head and neck. Providers indicated a major change in clinical management because of rWGS for 32% of infants tested overall and 70% of those with a diagnostic result. Also, 7% of infants with a negative rWGS result and 23% with a variant of unknown significance (VUS) had a major change in management due to testing. CONCLUSIONS: Our study demonstrates that the implementation of rWGS is feasible across diverse institutions, and provides additional evidence to support the clinical utility of rWGS in a demographically representative sample of admitted infants and includes assessment of the clinical impact of uncertain rWGS results in addition to both positive and negative results. PMID:38440187 | PMC:PMC10909823 | DOI:10.3389/fped.2024.1349519

February 19, 2024
RPM for NICU and PICUrWGSrWGS Efficacy

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

Kobren SN, Moldovan MA, Reimers R, Traviglia D, Li X, Barnum D, Veit A, Willett J, Berselli M, Ronchetti W, Sherwood R, Krier J, Kohane IS; Undiagnosed Diseases Network; Sunyaev SR.

bioRxiv [Preprint]. 2024 Feb 16:2024.02.13.580158. doi: 10.1101/2024.02.13.580158. ABSTRACT Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform “N-of-1” analyses on individual patients. The increasing sizes of ultra-rare, “N-of-1” disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale N-of-1 analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We apply existing and introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We make our gene-level findings and variant-level information across the cohort available in a public-facing browser ( These results show that N-of-1 efforts should be supplemented by a joint genomic analysis across cohorts. PMID:38405764 | PMC:PMC10888768 | DOI:10.1101/2024.02.13.580158

February 16, 2024
Rare Disease

Loss of symmetric cell division of apical neural progenitors drives DENND5A -related developmental and epileptic encephalopathy

Banks E, Francis V, Lin SJ, Kharfallah F, Fonov V, Levesque M, Han C, Kulasekaran G, Tuznik M, Bayati A, Al-Khater R, Alkuraya FS, Argyriou L, Babaei M, Bahlo M, Bakhshoodeh B, Barr E, Bartik L, Bassiony M, Bertrand M, Braun D, Buchert R, Budetta M, Cadieux-Dion M, Calame D, Cope H, Cushing D, Efthymiou S, Elmaksoud MA, El Said HG, Froukh T, Gill HK, Gleeson JG, Gogoll L, Goh ES, Gowda VK, Haack TB, Hashem MO, Hauser S, Hoffman TL, Hogue JS, Hosokawa A, Houlden H, Huang K, Huynh S, Karimiani EG, Kaulfuß S, Korenke GC, Kritzer A, Lee H, Lupski JR, Marco EJ, McWalter K, Minassian A, Minassian BA, Murphy D, Neira-Fresneda J, Northrup H, Nyaga D, Oehl-Jaschkowitz B, Osmond M, Person R, Pehlivan D, Petree C, Sadleir LG, Saunders C, Schoels L, Shashi V, Spillman RC, Srinivasan VM, Torbati PN, Tos T; Undiagnosed Diseases Network; Zaki MS, Zhou D, Zweier C, Trempe JF, Durcan TM, Gan-Or Z, Avoli M, Alves C, Varshney GK, Maroofian R, Rudko DA, McPherson PS.

medRxiv. 2024 Jan 31:2022.08.23.22278845. doi: 10.1101/2022.08.23.22278845. Preprint. ABSTRACT Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A -related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families. PMID:38352438 | PMC:PMC10863025 | DOI:10.1101/2022.08.23.22278845

January 31, 2024

The Plasma Lipidomic Landscape in Patients with Sepsis due to Community-acquired Pneumonia

Chouchane O, Schuurman AR, Reijnders TDY, Peters-Sengers H, Butler JM, Uhel F, Schultz MJ, Bonten MJ, Cremer OL, Calfee CS, Matthay MA, Langley RJ, Alipanah-Lechner N, Kingsmore SF, Rogers A, Weeghel MV, Vaz FM, van der Poll T.

Am J Respir Crit Care Med. 2024 Jan 19. doi: 10.1164/rccm.202308-1321OC. Online ahead of print. ABSTRACT RATIONALE: The plasma lipidome has the potential to reflect many facets of the host status during severe infection. Previous work is limited to specific lipid groups, or focused on lipids as prognosticators. OBJECTIVES: To map the plasma lipidome during sepsis due to community-acquired pneumonia (CAP), and determine disease-specificity and associations with clinical features. METHODS: We analyzed 1833 lipid species, across 33 classes, in 169 patients admitted to the intensive care unit (ICU) with sepsis due to CAP, 51 non-infected ICU patients and 48 outpatient controls. In a paired analysis we reanalyzed patients still in the ICU four days after admission (n=82). MEASUREMENTS AND MAIN RESULTS: 58% of plasma lipids were significantly lower in CAP-sepsis patients compared to outpatient controls (6% higher, 36% not different). We found strong, lipid class-specific associations with disease severity, validated across two external cohorts, and inflammatory biomarkers, in which triacylglycerols, cholesterol esters, and lysophospholipids exhibited the strongest associations. 36% of lipids increased over time, stratification by survival revealed diverging lipid recovery, which was confirmed in an external cohort; specifically, a 10% increase in cholesterol ester levels was related to a lower odds ratio (OR 0.84, p=0.006) for 30-day mortality (absolute mortality: 18/82). Comparison with non-infected ICU patients delineated a substantial common illness response (57.5%), and a lipidomic signal distinct for patients with CAP-sepsis (37%). CONCLUSIONS: Patients with sepsis due to CAP display a time-dependent and partially disease-specific shift in their plasma lipidome that correlates with disease severity and systemic inflammation, and is associated with higher mortality. PMID:38240721 | DOI:10.1164/rccm.202308-1321OC

January 19, 2024

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

Elkhateeb N, Issa MY, Elbendary HM, Elnaggar W, Ramadan A, Rafat K, Kamel M, Abdel-Ghafar SF, Amer F, Hassaan HM, Trunzo R, Pereira C, Abdel-Hamid MS, D’Arco F, Bauer P, Bertoli-Avella AM, Girgis M, Gleeson JG, Zaki MS, Selim L.

Clin Genet. 2024 Jan 14. doi: 10.1111/cge.14481. Online ahead of print. ABSTRACT Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients. PMID:38221827 | DOI:10.1111/cge.14481

January 14, 2024

Publications Question?

Contact Us About BeginNGS