Scientific Publications

396 Results

2021

Author Correction: Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Ross D, Stanley V, Sonmez FM, Topaloglu H, Zaki MS, Hosny H, Gad S, Gleeson JG.

Nat Commun. 2021 Feb 15;12(1):1192. doi: 10.1038/s41467-021-21448-1.

NO ABSTRACT

PMID:33589599 | PMC:PMC7884391 | DOI:10.1038/s41467-021-21448-1

February 16, 2021

Neurogenomics

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study

Maron JL, Kingsmore SF, Wigby K, Chowdhury S, Dimmock D, Poindexter B, Suhrie K, Vockley J, Diacovo T, Gelb BD, Stroustrup A, Powell CM, Trembath A, Gallen M, Mullen TE, Tanpaiboon P, Reed D, Kurfiss A, Davis JM.

JAMA Pediatr. 2021 Feb 15:e205906. doi: 10.1001/jamapediatrics.2020.5906. Online ahead of print. ABSTRACT IMPORTANCE: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. OBJECTIVE: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. DESIGN, SETTING, AND PARTICIPANTS: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. INTERVENTIONS: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. MAIN OUTCOMES AND MEASURES: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. RESULTS: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. CONCLUSIONS AND RELEVANCE: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood. PMID:33587123 | PMC:PMC7885094 | DOI:10.1001/jamapediatrics.2020.5906

February 15, 2021

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au KS, Hebert L, Hillman P, Baker C, Brown MR, Kim DK, Soldano K, Garrett M, Ashley-Koch A, Lee S, Gleeson J, Hixson JE, Morrison AC, Northrup H.

Sci Rep. 2021 Feb 11;11(1):3639. doi: 10.1038/s41598-021-83058-7. ABSTRACT Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort. PMID:33574475 | PMC:PMC7878900 | DOI:10.1038/s41598-021-83058-7

February 12, 2021

Emergence of an early SARS-CoV-2 epidemic in the United States

Zeller M, Gangavarapu K, Anderson C, Smither AR, Vanchiere JA, Rose R, Dudas G, Snyder DJ, Watts A, Matteson NL, Robles-Sikisaka R, Marshall M, Feehan AK, Sabino-Santos G, Bell-Kareem A, Hughes LD, Alkuzweny M, Snarski P, Garcia-Diaz J, Scott RS, Melnik LI, Klitting R, McGraw M, Belda-Ferre P, DeHoff P, Sathe S, Marotz C, Grubaugh N, Nolan DJ, Drouin AC, Genemaras KJ, Chao K, Topol S, Spencer E, Nicholson L, Aigner S, Yeo GW, Faranes L, Hobbs CA, Laurent LC, Knight R, Hodcroft EB, Khan K, Fusco DN, Cooper VS, Lemey P, Gardner L, Lamers SL, Kamil JP, Garry RF, Suchard MA, Andersen KG.

medRxiv [Preprint]. 2021 Feb 8:2021.02.05.21251235. doi: 10.1101/2021.02.05.21251235. PMID: 33564781; PMCID: PMC7872376.

Abstract

The emergence of the early COVID-19 epidemic in the United States (U.S.) went largely undetected, due to a lack of adequate testing and mitigation efforts. The city of New Orleans, Louisiana experienced one of the earliest and fastest accelerating outbreaks, coinciding with the annual Mardi Gras festival, which went ahead without precautions. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large, crowded events may have accelerated early transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana initially had limited sequence diversity compared to other U.S. states, and that one successful introduction of SARS-CoV-2 led to almost all of the early SARS-CoV-2 transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras and that the festival dramatically accelerated transmission, eventually leading to secondary localized COVID-19 epidemics throughout the Southern U.S.. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate COVID-19 epidemics on a local and regional scale. PMID: 33564781 | PMCID: PMC7872376 | DOI: 10.1101/2021.02.05.21251235

February 5, 2021

Capsule carbohydrate structure determines virulence in Acinetobacter baumannii

Talyansky Y, Nielsen TB, Yan J, Carlino-Macdonald U, Di Venanzio G, Chakravorty S, Ulhaq A, Feldman MF, Russo TA, Vinogradov E, Luna B, Wright MS, Adams MD, Spellberg B.

PLoS Pathog. 2021 Feb 2;17(2):e1009291. doi: 10.1371/journal.ppat.1009291. eCollection 2021 Feb. ABSTRACT Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis. PMID:33529209 | PMC:PMC7880449 | DOI:10.1371/journal.ppat.1009291

February 2, 2021

A Case of UDP-Galactose 4′-Epimerase Deficiency Associated with Dyshematopoiesis and Atrioventricular Valve Malformations: An Exceptional Clinical Phenotype Explained by Altered N-Glycosylation with Relative Preservation of the Leloir Pathway

Febres-Aldana CA, Pelaez L, Wright MS, Maher OM, Febres-Aldana AJ, Sasaki J, Jayakar P, Jayakar A, Diaz-Barbosa M, Janvier M, Totapally B, Salyakina D, Galvez-Silva JR.

Mol Syndromol. 2020 Dec;11(5-6):320-329. doi: 10.1159/000511343. Epub 2020 Oct 29. ABSTRACT The generalized form of UDP-galactose-4′-epimerase (GALE) deficiency causes hypotonia, failure to thrive, cataracts, and liver failure. Individuals with non-generalized forms may remain asymptomatic with uncertain long-term outcomes. We report a 2-year-old child compound heterozygous for GALE p.R51W/p.G237D who never developed symptoms of classic galactosemia but has a history of congenital combined mitral and tricuspid valve malformation and pyloric stenosis, and presented with pancytopenia. Variant pathogenicity was supported by predictive computational tools and decreased GALE activity measured in erythrocytes. GALE function extends to the biosynthesis of glycans by epimerization of UDP-N-acetyl-galactosamine and -glucosamine. Interrogation of the Gene Ontology consortium database revealed several putative proteins involved in normal hematopoiesis and atrioventricular valve morphogenesis, requiring N-glycosylation for adequate functionality. We hypothesize that by limiting substrate supply due to GALE deficiency, alterations in N-linked protein glycosylation can explain the patient’s phenotype. PMID:33510604 | PMC:PMC7802442 | DOI:10.1159/000511343

January 29, 2021

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients

Kuseyri Hübschmann O, Mohr A, Friedman J, Manti F, Horvath G, Cortès-Saladelafont E, Mercimek-Andrews S, Yildiz Y, Pons R, Kulhánek J, Oppebøen M, Koht JA, Podzamczer-Valls I, Domingo-Jimenez R, Ibáñez S, Alcoverro-Fortuny O, Gómez-Alemany T, de Castro P, Alfonsi C, Zafeiriou DI, López-Laso E, Guder P, Santer R, Honzík T, Hoffmann GF, Garbade SF, Sivri HS, Leuzzi V, Jeltsch K, García-Cazorla A, Opladen T; International Working Group on Neurotransmitter Related Disorders (iNTD), Harting I.

J Inherit Metab Dis. 2021 Jan 14. doi: 10.1002/jimd.12360. Online ahead of print. ABSTRACT Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction. PMID:33443316 | DOI:10.1002/jimd.12360

January 14, 2021

Genetic Neurologic Disease

Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy

Efthymiou S, Dutra-Clarke M, Maroofian R, Kaiyrzhanov R, Scala M, Reza Alvi J, Sultan T, Christoforou M, Tuyet Mai Nguyen T, Mankad K, Vona B, Rad A, Striano P, Salpietro V, Guillen Sacoto MJ, Zaki MS, Gleeson JG, Campeau PM, Russell BE, Houlden H.

Epilepsia. 2021 Feb;62(2):e35-e41. doi: 10.1111/epi.16801. Epub 2021 Jan 7. ABSTRACT The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy. PMID:33410539 | PMC:PMC7898547 | DOI:10.1111/epi.16801

January 7, 2021

Neurogenomics

Use of Plasma Metagenomic Next-generation Sequencing for Pathogen Identification in Pediatric Endocarditis

To RK, Ramchandar N, Gupta A, Pong A, Cannavino C, Foley J, Farnaes L, Coufal NG.

Pediatr Infect Dis J. 2020 Dec 30;Publish Ahead of Print. doi: 10.1097/INF.0000000000003038. Online ahead of print. ABSTRACT Pediatric infective endocarditis incurs significant morbidity and generally occurs among children with underlying heart disease. Identification of a pathogen is critical in determining appropriate therapy. However, standard diagnostic testing has limited sensitivity. We describe a case series of children with infective endocarditis in whom plasma next-generation sequencing (Karius, Redwood, CA) identified an organism in 8 of 10 cases. PMID:33410648 | DOI:10.1097/INF.0000000000003038

January 7, 2021

2020

The nucleotide prodrug CERC-913 improves mtDNA content in primary hepatocytes from DGUOK-deficient rats

Vanden Avond MA, Meng H, Beatka MJ, Helbling DC, Prom MJ, Sutton JL, Slick RA, Dimmock DP, Pertusati F, Serpi M, Pileggi E, Crutcher P, Thomas S, Lawlor MW.

J Inherit Metab Dis. 2021 Mar;44(2):492-501. doi: 10.1002/jimd.12354. Epub 2021 Jan 15. ABSTRACT Loss-of-function mutations in the deoxyguanosine kinase (DGUOK) gene result in a mitochondrial DNA (mtDNA) depletion syndrome. DGUOK plays an important role in converting deoxyribonucleosides to deoxyribonucleoside monophosphates via the salvage pathway for mtDNA synthesis. DGUOK deficiency manifests predominantly in the liver; the most common cause of death is liver failure within the first year of life and no therapeutic options are currently available. in vitro supplementation with deoxyguanosine or deoxyguanosine monophosphate (dGMP) were reported to rescue mtDNA depletion in DGUOK-deficient, patient-derived fibroblasts and myoblasts. CERC-913, a novel ProTide prodrug of dGMP, was designed to bypass defective DGUOK while improving permeability and stability relative to nucleoside monophosphates. To evaluate CERC-913 for its ability to rescue mtDNA depletion, we developed a primary hepatocyte culture model using liver tissue from DGUOK-deficient rats. DGUOK knockout rat hepatocyte cultures exhibit severely reduced mtDNA copy number (~10%) relative to wild type by qPCR and mtDNA content remains stable for up to 8 days in culture. CERC-913 increased mtDNA content in DGUOK-deficient hepatocytes up to 2.4-fold after 4 days of treatment in a dose-dependent fashion, which was significantly more effective than dGMP at similar concentrations. These early results suggest primary hepatocyte culture is a useful model for the study of mtDNA depletion syndromes and that CERC-913 treatment can improve mtDNA content in this model. PMID:33368311 | DOI:10.1002/jimd.12354

December 28, 2020

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