Browsing by Author "Dexheimer, Phillip J."

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    Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry
    (Oxford University Press, 2022) Erker, Craig; Lane, Adam; Chaney, Brooklyn; Leary, Sarah; Minturn, Jane E.; Bartels, Ute; Packer, Roger J.; Dorris, Kathleen; Gottardo, Nicholas G.; Warren, Katherine E.; Broniscer, Alberto; Kieran, Mark W.; Zhu, Xiaoting; White, Peter; Dexheimer, Phillip J.; Black, Katie; Asher, Anthony; DeWire, Mariko; Hansford, Jordan R.; Gururangan, Sridharan; Nazarian, Javad; Ziegler, David S.; Sandler, Eric; Bartlett, Allison; Goldman, Stewart; Shih, Chie-Schin; Hassall, Tim; Dholaria, Hetal; Bandopadhayay, Pratiti; Samson, Yvan; Monje, Michelle; Fisher, Paul G.; Dodgshun, Andrew; Parkin, Sarah; Chintagumpala, Murali; Tsui, Karen; Gass, David; Larouche, Valerie; Broxson, Emmett; Garcia Lombardi, Mercedes; Shiqi Wang, Stacie; Ma, Jie; Hawkins, Cynthia; Hamideh, Dima; Wagner, Lars; Koschmann, Carl; Fuller, Christine; Drissi, Rachid; Jones, Blaise V.; Leach, James; Fouladi, Maryam; Pediatrics, School of Medicine
    Background: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). Methods: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). Results: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. Conclusion: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
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    Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study
    (American Heart Association, 2021-05-04) Ware, Stephanie M.; Wilkinson, James D.; Tariq, Muhammad; Schubert, Jeffrey A.; Sridhar, Arthi; Colan, Steven D.; Shi, Ling; Canter, Charles E.; Hsu, Daphne T.; Webber, Steven A.; Dodd, Debra A.; Everitt, Melanie D.; Kantor, Paul F.; Addonizio, Linda J.; Jefferies, John L.; Rossano, Joseph W.; Pahl, Elfriede; Rusconi, Paolo; Chung, Wendy K.; Lee, Teresa; Towbin, Jeffrey A.; Lal, Ashwin K.; Bhatnagar, Surbhi; Aronow, Bruce; Dexheimer, Phillip J.; Martin, Lisa J.; Miller, Erin M.; Sleeper, Lynn A.; Razoky, Hiedy; Czachor, Jason; Lipshultz, Steven E.; Pediatrics, School of Medicine
    Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.
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    Mucosal Inflammatory and Wound Healing Gene Programmes Reveal Targets for Stricturing Behaviour in Paediatric Crohn’s Disease
    (Oxford University Press, 2020-08-08) Haberman, Yael; Minar, Phillip; Karns, Rebekah; Dexheimer, Phillip J.; Ghandikota, Sudhir; Tegge, Samuel; Shapiro, Daniel; Shuler, Brianne; Venkateswaran, Suresh; Braun, Tzipi; Ta, Allison; Walters, Thomas D.; Baldassano, Robert N.; Noe, Joshua D.; Rosh, Joel; Markowitz, James; Dotson, Jennifer L.; Mack, David R.; Kellermayer, Richard; Griffiths, Anne M.; Heyman, Melvin B.; Baker, Susan S.; Moulton, Dedrick; Patel, Ashish S.; Gulati, Ajay S.; Steiner, Steven J.; LeLeiko, Neal; Otley, Anthony; Oliva-Hemker, Maria; Ziring, David; Gokhale, Ranjana; Kim, Sandra; Guthery, Stephen L.; Cohen, Stanley A.; Snapper, Scott; Aronow, Bruce J.; Stephens, Michael; Gibson, Greg; Dillman, Jonathan R.; Dubinsky, Marla; Hyams, Jeffrey S.; Kugathasan, Subra; Jegga, Anil G.; Denson, Lee A.; Pediatrics, School of Medicine
    Background and aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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    The genetic architecture of pediatric cardiomyopathy
    (Elsevier, 2022) Ware, Stephanie M.; Bhatnagar, Surbhi; Dexheimer, Phillip J.; Wilkinson, James D.; Sridhar, Arthi; Fan, Xiao; Shen, Yufeng; Tariq, Muhammad; Schubert, Jeffrey A.; Colan, Steven D.; Shi, Ling; Canter, Charles E.; Hsu, Daphne T.; Bansal, Neha; Webber, Steven A.; Everitt, Melanie D.; Kantor, Paul F.; Rossano, Joseph W.; Pahl, Elfriede; Rusconi, Paolo; Lee, Teresa M.; Towbin, Jeffrey A.; Lal, Ashwin K.; Chung, Wendy K.; Miller, Erin M.; Aronow, Bruce; Martin, Lisa J.; Lipshultz, Steven E.; Pediatric Cardiomyopathy Registry Study Group; Pediatrics, School of Medicine
    To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
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    Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
    (Springer Nature, 2019-01-03) Haberman, Yael; Karns, Rebekah; Dexheimer, Phillip J.; Schirmer, Melanie; Somekh, Judith; Jurickova, Ingrid; Braun, Tzipi; Novak, Elizabeth; Bauman, Laura; Collins, Margaret H.; Mo, Angela; Rosen, Michael J.; Bonkowski, Erin; Gotman, Nathan; Marquis, Alison; Nistel, Mason; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; Leleiko, Neal S.; Heyman, Melvin B.; Grifiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Aronow, Bruce J.; Kugathasan, Subra; Walters, Thomas D.; Gibson, Greg; Thomas, Sonia Davis; Mollen, Kevin; Shen-Orr, Shai; Huttenhower, Curtis; Xavier, Ramnik J.; Hyams, Jeffrey S.; Denson, Lee A.; Pediatrics, School of Medicine
    Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.