Browsing by Author "Skotko, Brian G."

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    A randomized controlled trial of an online health tool about Down syndrome
    (Elsevier, 2021) Chung, Jeanhee; Donelan, Karen; Macklin, Eric A.; Schwartz, Alison; Elsharkawi, Ibrahim; Torres, Amy; Hsieh, Yichuan Grace; Parker, Holly; Lorenz, Stephen; Patsiogiannis, Vasiliki; Santoro, Stephanie L.; Wylie, Mark; Clarke, Lloyd; Estey, Greg; Baker, Sandra; Bauer, Patricia E.; Bull, Marilyn; Chicoine, Brian; Cullen, Sarah; Frey-Vogel, Ariel; Gallagher, Maureen; Hasan, Reem; Lamb, Ashley; Majewski, Lisa; Mast, Jawanda; Riddell, Travis; Sepucha, Karen; Skavlem, Melissa; Skotko, Brian G.; Pediatrics, School of Medicine
    Purpose: We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. Methods: In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs-personalized checklists-are used during annual wellness visits with the patient's PCP. Results: A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. Conclusions: DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.
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    Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging
    (Cell Press, 2019-09-05) Flex, Elisabetta; Martinelli, Simone; Van Dijck, Anke; Ciolfi, Andrea; Cecchetti, Serena; Coluzzi, Elisa; Pannone, Luca; Andreoli, Cristina; Radio, Francesca Clementina; Pizzi, Simone; Carpentieri, Giovanna; Bruselles, Alessandro; Catanzaro, Giuseppina; Pedace, Lucia; Miele, Evelina; Carcarino, Elena; Ge, Xiaoyan; Chijiwa, Chieko; Lewis, M.E. Suzanne; Meuwissen, Marije; Kenis, Sandra; Van der Aa, Nathalie; Larson, Austin; Brown, Kathleen; Wasserstein, Melissa P.; Skotko, Brian G.; Begtrup, Amber; Person, Richard; Karayiorgou, Maria; Roos, J. Louw; Van Gassen, Koen L.; Koopmans, Marije; Bijlsma, Emilia K.; Santen, Gijs W.E.; Barge-Schaapveld, Daniela Q.C.M.; Ruivenkamp, Claudia A.L.; Hoffer, Mariette J.V.; Lalani, Seema R.; Streff, Haley; Craigen, William J.; Graham, Brett H.; van den Elzen, Annette P.M.; Kamphuis, Daan J.; Ounap, Katrin; Reinson, Karit; Pajusalu, Sander; Wojcik, Monica H.; Viberti, Clara; Di Gaetano, Cornelia; Bertini, Enrico; Petrucci, Simona; De Luca, Alessandro; Rota, Rossella; Ferretti, Elisabetta; Matullo, Giuseppe; Dallapiccola, Bruno; Sgura, Antonella; Walkiewicz, Magdalena; Kooy, R. Frank; Tartaglia, Marco; Medical and Molecular Genetics, School of Medicine
    Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
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    Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study
    (MDPI, 2021-04-28) Hendrix, James A.; Airey, David C.; Britton, Angela; Burke, Anna D.; Capone, George T.; Chavez, Ronelyn; Chen, Jacqueline; Chicoine, Brian; Costa, Alberto C.S.; Dage, Jeffrey L.; Doran, Eric; Esbensen, Anna; Evans, Casey L.; Faber, Kelley M.; Foroud, Tatiana M.; Hart, Sarah; Haugen, Kelsey; Head, Elizabeth; Hendrix, Suzanne; Hillerstrom, Hampus; Kishnani, Priya S.; Krell, Kavita; Ledesma, Duvia Lara; Lai, Florence; Lott, Ira; Ochoa-Lubinoff, Cesar; Mason, Jennifer; Nicodemus-Johnson, Jessie; Proctor, Nicholas Kyle; Pulsifer, Margaret B.; Revta, Carolyn; Rosas, H. Diana; Rosser, Tracie C.; Santoro, Stephanie; Schafer, Kim; Scheidemantel, Thomas; Schmitt, Frederick; Skotko, Brian G.; Stasko, Melissa R.; Talboy, Amy; Torres, Amy; Wilmes, Kristi; Woodward, Jason; Zimmer, Jennifer A.; Feldman, Howard H.; Mobley, William; Medical and Molecular Genetics, School of Medicine
    With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.
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    A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay
    (Nature, 2018) Mucha, Bettina E.; Banka, Siddhart; Ajeawung, Norbert Fonya; Molidperee, Sirinart; Chen, Gary G.; Koenig, Mary Kay; Adejumo, Rhamat B.; Till, Marianne; Harbord, Michael; Perrier, Renee; Lemyre, Emmanuelle; Boucher, Renee-Myriam; Skotko, Brian G.; Waxler, Jessica L.; Thomas, Mary Ann; Hodge, Jennelle C.; Gecz, Jozef; Nicholl, Jillian; McGregor, Lesley; Linden, Tobias; Sisodiya, Sanjay M.; Sanlaville, Damien; Cheung, Sau W.; Ernst, Carl; Campeau, Philippe M.; Medical and Molecular Genetics, School of Medicine
    Purpose Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. Methods Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. Results All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. Conclusions We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.