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Browsing by Author "Gelb, Bruce D."
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Item Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum(Elsevier, 2020-09-03) Motta, Marialetizia; Pannone, Luca; Pantaleoni, Francesca; Bocchinfuso, Gianfranco; Radio, Francesca Clementina; Cecchetti, Serena; Ciolfi, Andrea; Di Rocco, Martina; Elting, Mariet W.; Brilstra, Eva H.; Boni, Stefania; Mazzanti, Laura; Tamburrino, Federica; Walsh, Larry; Payne, Katelyn; Fernández-Jaén, Alberto; Ganapathi, Mythily; Chung, Wendy K.; Grange, Dorothy K.; Dave-Wala, Ashita; Reshmi, Shalini C.; Bartholomew, Dennis W.; Mouhlas, Danielle; Carpentieri, Giovanna; Bruselles, Alessandro; Pizzi, Simone; Bellacchio, Emanuele; Piceci-Sparascio, Francesca; Lißewski, Christina; Brinkmann, Julia; Waclaw, Ronald R.; Waisfisz, Quinten; van Gassen, Koen; Wentzensen, Ingrid M.; Morrow, Michelle M.; Álvarez, Sara; Martínez-García, Mónica; De Luca, Alessandro; Memo, Luigi; Zampino, Giuseppe; Rossi, Cesare; Seri, Marco; Gelb, Bruce D.; Zenker, Martin; Dallapiccola, Bruno; Stella, Lorenzo; Prada, Carlos E.; Martinelli, Simone; Flex, Elisabetta; Tartaglia, Marco; Medical and Molecular Genetics, School of MedicineSignal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.Item Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes(Elsevier, 2018-02-01) Martinelli, Simone; Krumbach, Oliver H.F.; Pantaleoni, Francesca; Coppola, Simona; Amin, Ehsan; Pannone, Luca; Nouri, Kazem; Farina, Luciapia; Dvorsky, Radovan; Lepri, Francesca; Bucholzer, Marcel; Konopatzki, Raphael; Walsh, Laurence; Payne, Katelyn; Pierpont, Mary Ella; Vergano, Samantha Schrier; Langley, Katherine G.; Larsen, Douglas; Farwell, Kelly D.; Tang, Sha; Mroske, Cameron; Gallotta, Ivan; Schiavi, Elia Di; della Monica, Matteo; Lugli, Licia; Rossi, Cesare; Seri, Marco; Cocchi, Guido; Henderson, Lindsay; Baskin, Berivan; Alders, Mariëlle; Mendoza-Londono, Roberto; Dupuis, Lucie; Nickerson, Deborah A.; Chong, Jessica X.; Meeks, Naomi; Brown, Kathleen; Causey, Tahnee; Cho, Megan T.; Demuth, Stephanie; Digilio, Maria Cristina; Gelb, Bruce D.; Bamshad, Michael J.; Zenker, Martin; Ahmadian, Mohammad Reza; Hennekam, Raoul C.; Tartaglia, Marco; Mirzaa, Ghayda M.; Neurology, School of MedicineExome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.Item Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association(American Heart Association, 2021) Landstrom, Andrew P.; Kim, Jeffrey J.; Gelb, Bruce D.; Helm, Benjamin M.; Kannankeril, Prince J.; Semsarian, Christopher; Sturm, Amy C.; Tristani-Firouzi, Martin; Ware, Stephanie M.; Medical and Molecular Genetics, School of MedicineGenetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management, and prognosis. Although a number of guidelines and statements detail best practices for cardiovascular genetic testing, there is a paucity of pediatric-focused statements addressing the unique challenges in testing in this vulnerable population. In this scientific statement, we seek to coalesce the existing literature around the use of genetic testing for cardiovascular disease in infants, children, and adolescents.Item Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder(American Medical Association, 2023) Maron, Jill L.; Kingsmore, Stephen; Gelb, Bruce D.; Vockley, Jerry; Wigby, Kristen; Bragg, Jennifer; Stroustrup, Annemarie; Poindexter, Brenda; Suhrie, Kristen; Kim, Jae H.; Diacovo, Thomas; Powell, Cynthia M.; Trembath, Andrea; Guidugli, Lucia; Ellsworth, Katarzyna A.; Reed, Dallas; Kurfiss, Anne; Breeze, Janis L.; Trinquart, Ludovic; Davis, Jonathan M.; Pediatrics, School of MedicineImportance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test. Design, setting, and participants: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021. Exposure: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform. Main outcomes and measures: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care). Results: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis. Conclusions and relevance: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.Item The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery(Wiley, 2022) Kontaridis, Maria I.; Roberts, Amy E.; Schill, Lisa; Schoyer, Lisa; Stronach, Beth; Andelfinger, Gregor; Aoki, Yoko; Axelrad, Marni E.; Bakker, Annette; Bennett, Anton M.; Broniscer, Alberto; Castel, Pau; Chang, Caitlin A.; Cyganek, Lukas; Das, Tirtha K.; den Hertog, Jeroen; Galperin, Emilia; Garg, Shruti; Gelb, Bruce D.; Gordon, Kristiana; Green, Tamar; Gripp, Karen W.; Itkin, Maxim; Kiuru, Maija; Korf, Bruce R.; Livingstone, Jeff R.; López-Juárez, Alejandro; Magoulas, Pilar L.; Mansour, Sahar; Milner, Theresa; Parker, Elisabeth; Pierpont, Elizabeth I.; Plouffe, Kevin; Rauen, Katherine A.; Shankar, Suma P.; Smith, Shane B.; Stevenson, David A.; Tartaglia, Marco; Van, Richard; Wagner, Morgan E.; Ware, Stephanie M.; Zenker, Martin; Pediatrics, School of MedicineRASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen‐activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.Item Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome(Elsevier, 2020-07) Van Driest, Sara L.; Sleeper, Lynn A.; Gelb, Bruce D.; Morris, Shaine A.; Dietz, Harry C.; Forbus, Geoffrey A.; Goldmuntz, Elizabeth; Hoskoppal, Arvind; James, Jeanne; Lee, Teresa M.; Levine, Jami C.; Li, Jennifer S.; Loeys, Bart L.; Markham, Larry W.; Meester, Josephina A.N.; Mital, Seema; Mosley, Jonathan D.; Olson, Aaron K.; Renard, Marjolijn; Shaffer, Christian M.; Sharkey, Angela; Young, Luciana; Lacro, Ronald V.; Roden, Dan M.; Pediatrics, School of MedicineObjective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. Conclusions: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.