Scientific Publications

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229 Results

2022

Cord blood adiponectin and leptin are associated with a lower risk of stunting during infancy

Park S, Vargas Z, Zhao A, Baltazar PI, Friedman JF, McDonald EA.

Sci Rep. 2022 Sep 6;12(1):15122. doi: 10.1038/s41598-022-19463-3. ABSTRACT Undernutrition is responsible for up to 45% of deaths in children under five, with low- and middle-income countries disproportionately affected. Adipokines are known modulators of metabolism and have been linked to growth rates and neurocognition during infancy. We examined the relationship(s) between cord blood adiponectin and leptin and both longitudinal growth and cognition during the first year of life using generalized estimating equations. Infants were classified as underweight (weight-for-age z-score [WAZ]), stunted (height-for-age z-score [HAZ]) or wasted (weight-for-height z-score [WHZ]) using WHOAnthro software. Cord blood adiponectin and leptin levels were highly correlated (r = 0.35, P < 0.0001) and positively associated with birth WAZ (r = 0.34 and r = 0.45, P < 0.0001, respectively). Adipokines were independently, inversely associated with weight gain. Infants in the highest quintile of adipokine production had a lower risk of being stunted, while neither was associated with lower WAZ or WHZ in final adjusted models. Cognition was not found to be independently related to cord blood leptin or adiponectin. The negative association with adipokines and rate of weight gain during infancy may reflect heightened nutritional status at birth rather than a direct hormonal influence. The relationship between leptin or adiponectin and longitudinal length gains suggests that both adipokines may promote linear growth during infancy. PMID:36068284 | DOI:10.1038/s41598-022-19463-3

September 6, 2022
Genetic Neurologic Disease

“A novel serum extracellular vesicle protein signature to monitor glioblastoma tumor progression”

Tzaridis T, Weller J, Bachurski D, Shakeri F, Schaub C, Hau P, Buness A, Schlegel U, Steinbach JP, Seidel C, Goldbrunner R, Schäfer N, Wechsler-Reya RJ, Hallek M, Scheffler B, Glas M, Haeberle L, Herrlinger U, Coch C, Reiners KS, Hartmann G.

Int J Cancer. 2022 Aug 27. doi: 10.1002/ijc.34261. Online ahead of print. ABSTRACT Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In this study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n=67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA, and histone H3 as compared to serum EVs from healthy volunteers (p value range: <0.0001 – 0.08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44, and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA, and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA, and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making. PMID:36054558 | DOI:10.1002/ijc.34261

August 27, 2022
Neuro-Oncology

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

Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

Thomas Q, Motta M, Gautier T, Zaki MS, Ciolfi A, Paccaud J, Girodon F, Boespflug-Tanguy O, Besnard T, Kerkhof J, McConkey H, Masson A, Denommé-Pichon AS, Cogné B, Trochu E, Vignard V, El It F, Rodan LH, Alkhateeb MA, Jamra RA, Duplomb L, Tisserant E, Duffourd Y, Bruel AL, Jackson A, Banka S, McEntagart M, Saggar A, Gleeson JG, Sievert D, Bae H, Lee BH, Kwon K, Seo GH, Lee H, Saeed A, Anjum N, Cheema H, Alawbathani S, Khan I, Pinto-Basto J, Teoh J, Wong J, Sahari UBM, Houlden H, Zhelcheska K, Pannetier M, Awad MA, Lesieur-Sebellin M, Barcia G, Amiel J, Delanne J, Philippe C, Faivre L, Odent S, Bertoli-Avella A, Thauvin C, Sadikovic B, Reversade B, Maroofian R, Govin J, Tartaglia M, Vitobello A.

Am J Hum Genet. 2022 Aug 23:S0002-9297(22)00360-3. doi: 10.1016/j.ajhg.2022.08.008. Online ahead of print. ABSTRACT The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction. PMID:36044892 | DOI:10.1016/j.ajhg.2022.08.008

August 23, 2022
Neurogenomics

Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts

Leskoske KL, Garcia-Mansfield K, Sharma R, Krishnan A, Rusert JM, Mesirov JP, Wechsler-Reya RJ, Pirrotte P.

J Proteome Res. 2022 Aug 17. doi: 10.1021/acs.jproteome.2c00203. Online ahead of print. ABSTRACT Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070. PMID:35977718 | DOI:10.1021/acs.jproteome.2c00203

August 17, 2022
Genetic Neurologic Disease

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Dias KR, Carlston CM, Blok LER, De Hayr L, Nawaz U, Evans CA, Bayrak-Toydemir P, Htun S, Zhu Y, Ma A, Lynch SA, Moorwood C, Stals K, Ellard S, Bainbridge MN, Friedman J, Pappas JG, Rabin R, Nowak CB, Douglas J, Wilson TE, Guillen Sacoto MJ, Mullegama SV, Palculict TB, Kirk EP, Pinner JR, Edwards M, Montanari F, Graziano C, Pippucci T, Dingmann B, Glass I, Mefford HC, Shimoji T, Suzuki T, Yamakawa K, Streff H, Schaaf CP, Slavotinek AM, Voineagu I, Carey JC, Buckley MF, Schenck A, Harvey RJ, Roscioli T.

Genet Med. 2022 Aug 1:S1098-3600(22)00803-6. doi: 10.1016/j.gim.2022.06.001. Online ahead of print. ABSTRACT PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability. PMID:35916866 | DOI:10.1016/j.gim.2022.06.001

August 1, 2022
Genetic Neurologic Disease

Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability

Bae T, Fasching L, Wang Y, Shin JH, Suvakov M, Jang Y, Norton S, Dias C, Mariani J, Jourdon A, Wu F, Panda A, Pattni R, Chahine Y, Yeh R, Roberts RC, Huttner A, Kleinman JE, Hyde TM, Straub RE, Walsh CA; Brain Somatic Mosaicism Network§, Urban AE, Leckman JF, Weinberger DR, Vaccarino FM, Abyzov A, Walsh CA, Park PJ, Sestan N, Weinberger D, Moran JV, Gage FH, Vaccarino FM, Gleeson J, Mathern G, Courchesne E, Roy S, Chess AJ, Akbarian S, Bizzotto S, Coulter M, Dias C, D’Gama A, Ganz J, Hill R, Huang AY, Khoshkhoo S, Kim S, Lee A, Lodato M, Maury EA, Miller M, Borges-Monroy R, Rodin R, Zhou Z, Bohrson C, Chu C, Cortes-Ciriano I, Dou Y, Galor A, Gulhan D, Kwon M, Luquette J, Sherman M, Viswanadham V, Jones A, Rosenbluh C, Cho S, Langmead B, Thorpe J, Erwin J, Jaffe A, McConnell M, Narurkar R, Paquola A, Shin J, Straub R, Abyzov A, Bae T, Jang Y, Wang Y, Molitor C, Peters M, Linker S, Reed P, Wang M, Urban A, Zhou B, Zhu X, Pattni R, Serres Amero A, Juan D, Lobon I, Marques-Bonet T, Solis Moruno M, Garcia Perez R, Povolotskaya I, Soriano E, Antaki D, Averbuj D, Ball L, Breuss M, Yang X, Chung C, Emery SB, Flasch DA, Kidd JM, Kopera HC, Kwan KY, Mills RE, Moldovan JB, Sun C, Zhao X, Zhou W, Frisbie TJ, Cherskov A, Fasching L, Jourdon A, Pochareddy S, Scuderi S.

Science. 2022 Jul 29;377(6605):511-517. doi: 10.1126/science.abm6222. Epub 2022 Jul 28. ABSTRACT We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism. PMID:35901164 | DOI:10.1126/science.abm6222

July 29, 2022
Neurogenomics

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
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

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