114 results on '"G. Bradley Schaefer"'
Search Results
2. Diagnosis of Charcot–Marie–Tooth Disease in a Patient With Decreased Vision From Optic Atrophy and No Other Neurological Symptoms
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Joseph A. Chacko, Paul H. Phillips, Raghu H. Ramakrishnaiah, G. Bradley Schaefer, and Sami H. Uwaydat
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Ophthalmology ,Neurology (clinical) - Published
- 2022
3. P354: An apparently new brain MRI finding in Sotos syndrome: Extensively dilated perivascular spaces
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Leah Wibecan, Angela Lin, Karen Buch, Otto Rapalino, Frances High, Ashley Wong, Dorit Koren, G. Bradley Schaefer, and Danielle Pier
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- 2023
4. Author Correction: Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
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Renske Oegema, Vinodh Narayanan, Marleen Simon, Trudie Cottrell, Marie-Christine Nougues, Mieke M. van Haelst, Gijs W. E. Santen, Roger E. Stevenson, Keri Ramsey, Kay Metcalfe, Jacques C. Giltay, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marielle Alders, Hannah W. Moore, Claudia A. L. Ruivenkamp, Jessica Bos, Richard H. van Jaarsveld, Jill A. Fahrner, David B. Beck, Sofia Douzgou, Jennifer Kerkhof, Muhammad Ansar, Michael A. Levy, G. Bradley Schaefer, Siddharth Banka, Roberto Bonasio, Kimberly F. Doheny, M. Mahdi Motazacker, Cyril Mignot, Elles M. J. Boon, Boris Keren, and Bekim Sadikovic
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Genetics ,Medicine ,Dna hypermethylation ,QH426-470 ,Biology ,Molecular Biology ,Genome ,Genetics (clinical) ,Whole blood - Published
- 2021
5. Pathogenic in-Frame Variants in
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Jennifer C, Wong, Kameryn M, Butler, Lindsey, Shapiro, Jacquelyn T, Thelin, Kari A, Mattison, Kathryn B, Garber, Paula C, Goldenberg, Shobana, Kubendran, G Bradley, Schaefer, and Andrew, Escayg
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Pharmacology ,SCN8A ,seizure ,epilepsy ,mutation ,mouse ,Original Research ,sodium channel - Abstract
Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.
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- 2021
6. Molecular Dysregulation in Autism Spectrum Disorder
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Patricia Porter-Gill, Harsh Dweep, Jeffery L Clothier, Aravindhan Veerapandiyan, G. Bradley Schaefer, and Pritmohinder S. Gill
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pharmacogenomics ,Candidate gene ,knockout models ,Medicine (miscellaneous) ,Single-nucleotide polymorphism ,Computational biology ,Review ,Biology ,medicine.disease ,endophenotypes ,Biomarker (cell) ,copy number variation (CNV) ,Autism spectrum disorder ,Pharmacogenomics ,Endophenotype ,mental disorders ,medicine ,autism spectrum disorder (ASD) ,Medicine ,biomarker ,Copy-number variation ,genetic ,Exome sequencing ,epigenetic - Abstract
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.
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- 2021
7. De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities
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Volkan Okur, Zefu Chen, Liesbeth Vossaert, Sandra Peacock, Jill Rosenfeld, Lina Zhao, Haowei Du, Emily Calamaro, Amanda Gerard, Sen Zhao, Jill Kelsay, Ashley Lahr, Chloe Mighton, Hillary M. Porter, Amy Siemon, Josh Silver, Shayna Svihovec, Chin-To Fong, Christina L. Grant, Jordan Lerner-Ellis, Kandamurugu Manickam, Suneeta Madan-Khetarpal, Shawn E. McCandless, Chantal F. Morel, G. Bradley Schaefer, Elizabeth M. Berry-Kravis, Ryan Gates, Natalia Gomez-Ospina, Guixing Qiu, Terry Jianguo Zhang, Zhihong Wu, Linyan Meng, Pengfei Liu, Daryl A. Scott, James R. Lupski, Christine M. Eng, Nan Wu, and Bo Yuan
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Genetic testing ,Molecular medicine ,Genetics research ,Neurodevelopmental disorders ,Genetics ,Medicine ,QH426-470 ,Molecular Biology ,Genetics (clinical) ,Article - Abstract
The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
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- 2021
8. Implementing Pharmacogenomics Testing: Single Center Experience at Arkansas Children's Hospital
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Jeffery L Clothier, Feliciano B. Yu, Aravindhan Veerapandiyan, David L. Becton, Bobby L. Boyanton, Kevin Bielamowicz, Judy C Allen, Andrew Burrow, Parthak Prodhan, Elizabeth A. Sellars, G. Bradley Schaefer, Joshua L. Kennedy, Don Rule, Patricia Porter-Gill, Jason E. Farrar, and Pritmohinder S. Gill
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medicine.medical_specialty ,pediatrics ,phenotype ,genotype ,Medicine (miscellaneous) ,EPIC ,Single Center ,030226 pharmacology & pharmacy ,Clinical decision support system ,Article ,03 medical and health sciences ,0302 clinical medicine ,electronic health records (EHR) ,medicine ,Dosing ,Intensive care medicine ,Adverse effect ,business.industry ,clinical decision support (CDS) ,pharmacogenomics (PGx) ,Precision medicine ,030220 oncology & carcinogenesis ,Pharmacogenomics ,best practice alerts (BPAs) ,Medicine ,Biomarker (medicine) ,genomic indicators ,business - Abstract
Pharmacogenomics (PGx) is a growing field within precision medicine. Testing can help predict adverse events and sub-therapeutic response risks of certain medications. To date, the US FDA lists over 280 drugs which provide biomarker-based dosing guidance for adults and children. At Arkansas Children’s Hospital (ACH), a clinical PGx laboratory-based test was developed and implemented to provide guidance on 66 pediatric medications for genotype-guided dosing. This PGx test consists of 174 single nucleotide polymorphisms (SNPs) targeting 23 clinically actionable PGx genes or gene variants. Individual genotypes are processed to provide per-gene discrete results in star-allele and phenotype format. These results are then integrated into EPIC- EHR. Genomic indicators built into EPIC-EHR provide the source for clinical decision support (CDS) for clinicians, providing genotype-guided dosing.
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- 2021
9. Multidisciplinary Consulting Team for Complicated Cases of Neurodevelopmental and Neurobehavioral Disorders: Assessing the Opportunities and Challenges of Integrating Pharmacogenomics into a Team Setting
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Pritmohinder S. Gill, Amanda L. Elchynski, Patricia A. Porter-Gill, Bradley G. Goodson, Mary Ann Scott, Damon Lipinski, Amy Seay, Christina Kehn, Tonya Balmakund, and G. Bradley Schaefer
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neurodevelopmental disorders ,autism spectrum disorder ,ADHD ,pharmacogenomics ,CYP2D6 ,CYP2C19 ,phenoconversion ,Medicine (miscellaneous) - Abstract
Neurodevelopmental disorders have steadily increased in incidence in the United States. Over the past decade, there have been significant changes in clinical diagnoses and treatments some of which are due to the increasing adoption of pharmacogenomics (PGx) by clinicians. In this pilot study, a multidisciplinary team at the Arkansas Children’s Hospital North West consulted on 27 patients referred for difficult-to-manage neurodevelopmental and/or neurobehavioral disorders. The 27 patients were evaluated by the team using records review, team discussion, and pharmacogenetic testing. OneOme RightMed® (Minneapolis, MN, USA) and the Arkansas Children’s Hospital comprehensive PGx test were used for drug prescribing guidance. Of the 27 patients’ predicted phenotypes, the normal metabolizer was 11 (40.8%) for CYP2C19 and 16 (59.3%) for CYP2D6. For the neurodevelopmental disorders, the most common comorbid conditions included attention-deficit hyperactivity disorder (66.7%), anxiety disorder (59.3%), and autism (40.7%). Following the team assessment and PGx testing, 66.7% of the patients had actionable medication recommendations. This included continuing current therapy, suggesting an appropriate alternative medication, starting a new therapy, or adding adjunct therapy (based on their current medication use). Moreover, 25.9% of patients phenoconverted to a CYP2D6 poor metabolizer. This retrospective chart review pilot study highlights the value of a multidisciplinary treatment approach to deliver precision healthcare by improving physician clinical decisions and potentially impacting patient outcomes. It also shows the feasibility to implement PGx testing in neurodevelopmental/neurobehavioral disorders.
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- 2022
10. Rates of diagnostic genetic testing in a tertiary ocular genetics clinic
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G. Bradley Schaefer, Sami H. Uwaydat, John R. Dehnel, and R. Scott Lowery
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medicine.medical_specialty ,medicine.diagnostic_test ,Eye Diseases ,business.industry ,Disease ,Ophthalmology ,Phenotype ,Pediatrics, Perinatology and Child Health ,Patient experience ,Genetics clinic ,medicine ,Medical genetics ,Humans ,Genetic Testing ,Intensive care medicine ,business ,Genetics (clinical) ,Genetic testing ,Retrospective Studies - Abstract
Clinical genetics has evolved significantly to become an efficient and effective means of diagnosing disease. Genetic treatments are now being developed which are showing promising results. However, ophthalmic patients are not utilizing genetic testing as part of their diagnostic workups. This paper explores the patient experience at the Ocular Genetics Clinic (OGC) at the University of Arkansas for Medical Sciences (UAMS) Jones Eye Institute and discusses reasons why patients continue to not pursue genetic testing.We performed a retrospective chart review to understand the main reasons why patients were referred to the OGC between 2009 and 2018, with a detailed analysis of why patients did not pursue genetic testing.Patients mainly did not undergo testing due to the cost of testing. However, patient availability, patient interest, and diagnostic workup also drove a significant amount of this lack of testing.Ocular genetic testing is becoming an increasingly beneficial tool for diagnosing ocular disease. However, to date, patients do not utilize this service fully. At the OGC, there are several main drivers for this lack of testing, namely finances, interest/availability, and diagnostic workup. As more ocular genetics clinics are established, it will be imperative to address reasons for forgoing genetic testing and to develop strategies to encourage patients to pursue this testing.
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- 2020
11. De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy
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Bobby P. C. Koeleman, Volker Mall, Wen-Hann Tan, Rachel Slaugh, Ralitza H. Gavrilova, Yue Si, Shelley Towner, Aditi Gupta, Emily Bryant, Yasemin Dincer, Matias Wagner, Michael Zech, Sakshi Singh, Koen L.I. van Gassen, Jorge L. Granadillo, Rhonda E. Schnur, Nicole P. Safina, Ashley N. Sigafoos, Eric W. Klee, Jennifer B. Humberson, Eva H. Brilstra, Sunita N. Misra, Tracy Brandt, Juliane Winkelmann, Francisca Millan, Sarah R Green, Kendra Engleman, Karl J. Clark, and G. Bradley Schaefer
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NR4A2 ,Biology ,Brief Communication ,Epilepsy ,Developmental Disorder ,Neurodevelopmental Disorder ,Nr4a2 ,Seizures ,Neurodevelopmental disorder ,Intellectual Disability ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Exome Sequencing ,medicine ,Missense mutation ,Humans ,Gene ,Genetics (clinical) ,Exome sequencing ,developmental disorder ,seizures ,Genetics ,medicine.disease ,neurodevelopmental disorder ,Hypotonia ,ddc ,Developmental disorder ,Phenotype ,Neurodevelopmental Disorders ,RNA splicing ,Muscle Hypotonia ,medicine.symptom - Abstract
Purpose: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.
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- 2019
12. Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features
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Alan Fryer, Rolph Pfundt, Lori A. Carpenter, Susan M. White, Kirsten P. Forbes, Daniela T. Pilz, Nava Shaul-Lotan, Andrew E. Fry, Anthonie J. van Essen, Amy E. Roberts, A. Micheil Innes, Katherine A. Fawcett, Beatriz Paumard-Hernández, Michael Wright, Peter D. Turnpenny, Blanca Gener, Richard Caswell, Lindsay B. Henderson, Romana Gjergja-Juraski, Melissa Sloman, Wendy K. Chung, Karen E. Heath, G. Bradley Schaefer, Heather M. McLaughlin, and Erica H. Gerkes
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0301 basic medicine ,EXPRESSION ,PCGF2 ,Polycomb Group Ring Finger 2 ,MEL-18 ,Mutant ,dysmorphism ,PROTEIN ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Report ,Histone H2A ,Genetics ,Gene silencing ,Missense mutation ,polymicrogyria ,Craniofacial ,SPECIFICATION ,Gene ,MEL18 ,intellectual disability ,Genetics (clinical) ,CYCLIN D2 ,UBIQUITYLATION ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,REPRESSION ,Correction ,Phenotype ,GENE ,030104 developmental biology ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,HISTONE H2A ,STEM-CELLS - Abstract
PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.
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- 2018
13. Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
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Tiia Reimand, Kirsty McWalter, Eleanor G. Seaby, G. Bradley Schaefer, Marwan Shinawi, Muhammad Arif Nadeem Saqib, Aida Telegrafi, Ana Petracovici, Sander Pajusalu, Jill A. Fahrner, David B. Beck, Chongsheng He, Hannah W. Moore, Suzanne M. Leal, Raymond J. Louie, Siddharth Banka, Renee Bend, Regie Lyn P. Santos-Cortez, Roberto Bonasio, Boris Keren, Marie Christine Nougues, Eloise J. Prijoles, Muhammad Ansar, Katrin Õunap, Roger E. Stevenson, Julien Buratti, Sofia Douzgou, Cyril Mignot, Sivagamy Sithambaram, Trudie Cottrell, Dustin Baldridge, and Muhammad Zahid
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0301 basic medicine ,Adult ,Male ,Protein Conformation ,Developmental Disabilities ,Embryonic Development ,Sequence Homology ,Frameshift mutation ,Dioxygenases ,03 medical and health sciences ,symbols.namesake ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Report ,Genetics ,Humans ,Epigenetics ,Amino Acid Sequence ,Autistic Disorder ,Child ,Genetics (clinical) ,Growth Disorders ,5-Hydroxymethylcytosine ,Movement Disorders ,biology ,Gene Expression Regulation, Developmental ,Infant ,Middle Aged ,Pedigree ,DNA Demethylation ,5-Methylcytosine ,030104 developmental biology ,Histone ,DNA demethylation ,chemistry ,Child, Preschool ,DNA methylation ,biology.protein ,Mendelian inheritance ,symbols ,Female ,030217 neurology & neurosurgery - Abstract
Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
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- 2019
14. The ubiquitin ligase UBE3B, disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK
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Nadine Nijem, Maria J. Guillen-Sacoto, Pooja Kumar, Paige Kaplan, Maria H. Chahrour, G. Bradley Schaefer, Solmi Cheon, Prashant Mishra, Islam Oguz Tuncay, Kiran J Kaur, Emma Bedoukian, Milan Dean, Jane Juusola, and Lynne Ierardi-Curto
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0301 basic medicine ,Adult ,Male ,Adolescent ,Ubiquitin-Protein Ligases ,BCKDK ,Limb Deformities, Congenital ,medicine.disease_cause ,Compound heterozygosity ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neurodevelopmental disorder ,Ubiquitin ,Intellectual Disability ,medicine ,Animals ,Humans ,Language Development Disorders ,Eye Abnormalities ,Child ,Mice, Knockout ,Mutation ,Multidisciplinary ,biology ,Kinase ,Skeletal muscle ,Brain ,Facies ,Biological Sciences ,medicine.disease ,Cell biology ,Ubiquitin ligase ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,biology.protein ,Microcephaly ,Protein Kinases ,030217 neurology & neurosurgery ,Metabolic Networks and Pathways - Abstract
Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b(−/−) mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b(−/−) cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b(−/−) mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b(−/−) mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.
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- 2019
15. De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia
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Coranne D. Tesselaar, Usha Kini, Vandana Shashi, Willie Reardon, H. T. Marc Timmers, Donna M. Martin, Jenny C. Taylor, Dong Li, Elizabeth M. McCormick, Alice Goldenberg, Marketa Havlovicova, Peter M. van Hasselt, Harmjan R. Vos, Maria J.E. Koster, Daphné Lehalle, Sophie Patrier, Elena Lopez, Rolph Pfundt, Richard F.M.A. van Schaik, Koen L.I. van Gassen, Gerarda Cappuccio, Julien Thevenon, Clesson Turner, Ingrid M.B.H. van de Laar, Marni J. Falk, Marketa Vlckova, Vassilis Ragoussis, Robert M. van Es, Nicola Brunetti-Pierri, Michele Pinelli, Alistair T. Pagnamenta, Christina Fagerberg, Darina Prchalova, Slavé Petrovski, Anna Lehman, Hakon Hakonarson, Ton van Essen, Maria Kibaek, Hanneke A. Haijes, G. Bradley Schaefer, Miroslava Hancarova, Jennifer A. Sullivan, Sedlácek Z, Holger Rehmann, Clinical Genetics, Haijes, Hanneke A, Koster, Maria J E, Rehmann, Holger, Li, Dong, Hakonarson, Hakon, Cappuccio, Gerarda, Hancarova, Miroslava, Lehalle, Daphne, Reardon, Willie, Schaefer, G Bradley, Lehman, Anna, van de Laar, Ingrid M B H, Tesselaar, Coranne D, Turner, Clesson, Goldenberg, Alice, Patrier, Sophie, Thevenon, Julien, Pinelli, Michele, Brunetti-Pierri, Nicola, Prchalová, Darina, Havlovicová, Markéta, Vlckova, Markéta, Sedláček, Zdeněk, Lopez, Elena, Ragoussis, Vassili, Pagnamenta, Alistair T, Kini, Usha, Vos, Harmjan R, van Es, Robert M, van Schaik, Richard F M A, van Essen, Ton A J, Kibaek, Maria, Taylor, Jenny C, Sullivan, Jennifer, Shashi, Vandana, Petrovski, Slave, Fagerberg, Christina, Martin, Donna M, van Gassen, Koen L I, Pfundt, Rolph, Falk, Marni J, Mccormick, Elizabeth M, Timmers, H T Marc, and van Hasselt, Peter M
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Male ,Muscle Hypotonia ,POLR2A ,PROTEIN ,RNA polymerase II ,ELONGATION COMPLEX ,INITIATION ,0302 clinical medicine ,infantile-onset hypotonia ,Transcription (biology) ,PROGRAM ,Missense mutation ,Genetics(clinical) ,TRANSCRIPTION ,Age of Onset ,Child ,MUTATION ,de novo variants ,Genetics (clinical) ,RNA polymerase II complex ,Genetics ,0303 health sciences ,haplo-insufficiency ,DNA-Directed RNA Polymerases ,dominant-negative effect ,Hypotonia ,Phenotype ,Child, Preschool ,Female ,medicine.symptom ,LARGEST SUBUNIT ,STRUCTURAL BASIS ,Heterozygote ,Adolescent ,RNA-POLYMERASE-II ,Saccharomyces cerevisiae ,Biology ,Article ,RPB1 ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,desert Z score ,medicine ,Humans ,CELL-CYCLE ,Allele ,Gene ,030304 developmental biology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,neurodevelopmental syndrome ,Neurodevelopmental Disorders ,biology.protein ,desert regions ,de novo variant ,desert region ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
The RNA polymerase II complex (pol II) is responsible for transcription of all similar to 21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
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- 2019
16. Genetic Considerations in Infants with Congenital Anomalies
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Elizabeth A. Sellars and G. Bradley Schaefer
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Newborn screening ,Pediatrics ,medicine.medical_specialty ,business.industry ,Medicine ,After discharge ,business ,Healthcare providers - Abstract
Congenital anomalies or birth defects account for one of the leading causes of death in infants. When one anomaly is present, there is a 50% risk that other anomalies are present. Healthcare providers taking care of newborns should have a low threshold to look for additional anomalies in the presence of one. These anomalies may not always be identified in the hospital but may require evaluation after discharge. Close attention to the type and pattern of anomalies also provides clues to the underlying diagnosis. Genetic consultation is critical to help identify patterns and guide appropriate testing, especially in this time of ever-changing and complex diagnostic options.
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- 2018
17. Clinical experience in an ocular genetics tertiary care clinic
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G. Bradley Schaefer, John R. Dehnel, Robert S. Lowery, and Sami H. Uwaydat
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Ophthalmology ,medicine.medical_specialty ,business.industry ,Family medicine ,Pediatrics, Perinatology and Child Health ,medicine ,business ,Tertiary care - Published
- 2019
18. Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation
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Ludwine Messiaen, Ashley Cannon, Concepción Hernández-Chico, Yolanda Martin, Andrea Shugar, Mary Ella M Pierpont, Robert S. Greenwood, Yunjia Chen, Fortunato Lonardo, Ellen Denayer, Arthur S. Aylsworth, Shelley K. Dills, Mayra Martinez Ojeda, Elizabeth K. Schorry, Amedeo A. Azizi, Lois J. Starr, Andrea M. Lewis, Rianne Oostenbrink, Bruce R. Korf, Pamela Trapane, Peter Kannu, Daryl A. Scott, Elizabeth Siqveland, Rick van Minkelen, Justin T. Jordan, Laura Dosa, Nancy J. Mendelsohn, David T. Miller, Dinel A. Pond, Alessandro De Luca, Elaine H. Zackai, Rachel K. Hachen, Donald Basel, Linda M. Randolph, Eric Legius, Maurice J. Mahoney, Tom Callens, Maria Cristina Digilio, Alesha D. Hicks, Carmelo Piscopo, Sandra Janssens, Katherine A. Rauen, Michael F. Wangler, Ashraf Syed, Emily Wakefield, Punita Gupta, Lynne M. Bird, Alicia Gomes, Marie T. McDonald, Katharina Wimmer, S. Lane Rutledge, Colette DeFilippo, Robert Listernick, Kathleen Claes, Surya P. Rednam, Nicole J. Ullrich, Leah W. Burke, Carey McDougall, Sébastien Perreault, Gary Bellus, Magdalena Koczkowska, Cristin Griffis, Laurence E. Walsh, Angela Sharp, Felicity Collins, Maria Blazo, Kristi J. Jones, Mari Mori, Veronica Saletti, and G. Bradley Schaefer
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Genetics ,Correlation ,Frame (networking) ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Biology ,Clinical phenotype ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Gene ,Genetics (clinical) ,Genotype phenotype - Abstract
A correction has been published to this Article. The PDF and HTML have been updated accordingly.
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- 2019
19. Myhre syndrome: Clinical features and restrictive cardiopulmonary complications
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Jeffrey W. Delaney, Ann Haskins Olney, Jennifer N. Sanmann, Deborah Perry, Dorothy K. Grange, James M. Hammel, Anji T. Yetman, G. Bradley Schaefer, and Lois J. Starr
- Subjects
Male ,medicine.medical_specialty ,Heart Diseases ,Electrocardiography ,Young Adult ,Pericarditis ,Pregnancy ,Fibrosis ,Intellectual Disability ,Ductus arteriosus ,Internal medicine ,Cryptorchidism ,Genetics ,medicine ,Humans ,Pulmonary pathology ,Myhre syndrome ,Child ,Growth Disorders ,Genetics (clinical) ,Smad4 Protein ,business.industry ,Restrictive cardiomyopathy ,Facies ,medicine.disease ,Transplantation ,medicine.anatomical_structure ,Mutation ,Cardiology ,Heart Transplantation ,Female ,Complication ,business ,Hand Deformities, Congenital - Abstract
Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.
- Published
- 2015
20. Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors
- Author
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Thomas C. Markello, Stephen G. Kahler, Noelle R. Danylchuk, Gretchen Golas, Irina Maric, Lynne A. Wolfe, Adolfo Garnica, Maya Lodish, Wadih M. Zein, David R. Adams, Constantine A. Stratakis, Eva H. Baker, G. Bradley Schaefer, May Christine V. Malicdan, Sergio D. Rosenzweig, William A. Gahl, Andrea L. Gropman, Christina Lam, Megan S. Kane, Carlos Ferreira, Cornelius F. Boerkoel, Donna M. Krasnewich, Marjan Huizing, and Mariska Davids
- Subjects
Heterozygote ,Glycosylphosphatidylinositols ,Intellectual and Developmental Disabilities (IDD) ,Developmental Disabilities ,Endocrinology, Diabetes and Metabolism ,Clinical Sciences ,Mutation, Missense ,Glycosylphosphatidylinositol anchor ,Biology ,Compound heterozygosity ,Biochemistry ,Article ,Frameshift mutation ,Congenital ,Endocrinology ,Clinical Research ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Humans ,Missense mutation ,Exome ,Flow cytometry ,Global developmental delay ,Aetiology ,Child ,Frameshift Mutation ,Molecular Biology ,Exome sequencing ,Skin ,Pediatric ,Genetics & Heredity ,Congenital disorder of glycosylation ,Fibroblasts ,medicine.disease ,Hypotonia ,Brain Disorders ,Phenotype ,Mutation ,Congenital Structural Anomalies ,Muscle Hypotonia ,Missense ,PIGT-CDG ,medicine.symptom ,Acyltransferases - Abstract
PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C>T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.
- Published
- 2015
21. Adults' perceptions of genetic counseling and genetic testing
- Author
-
Gwendolyn M. Reiser, Brigette Soltis-Vaughan, Jan R. Atwood, G. Bradley Schaefer, and Julia F. Houfek
- Subjects
Adult ,Male ,Patients ,Genetic counseling ,media_common.quotation_subject ,Early detection ,Genetic Counseling ,Disease ,Surveys and Questionnaires ,Perception ,Humans ,Medicine ,Genetic Testing ,General Nursing ,Aged ,Genetic testing ,media_common ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Psychological distress ,Middle Aged ,Test (assessment) ,Female ,business ,Clinical psychology ,Patient education - Abstract
Purpose This study described the perceptions of genetic counseling and testing of adults ( N =116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. Methods Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. Results Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. Conclusions Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles.
- Published
- 2015
22. Aplastic Anemia in Two Patients with Sex Chromosome Aneuploidies
- Author
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G. Bradley Schaefer, Peter F. Coccia, Warren G. Sanger, and Eric T. Rush
- Subjects
Pediatrics ,medicine.medical_specialty ,Adolescent ,Anemia ,Sex Chromosome Disorders of Sex Development ,Trisomy ,Opportunistic Infections ,Biology ,Craniofacial Abnormalities ,Intellectual Disability ,Genetics ,medicine ,Humans ,Risk factor ,Aplastic anemia ,Molecular Biology ,Sex Chromosome Aberrations ,Genetics (clinical) ,Bone Marrow Transplantation ,Chromosomes, Human, X ,Incidence (epidemiology) ,Graft Survival ,Anemia, Aplastic ,Chromosome ,Karyotype ,medicine.disease ,Treatment Outcome ,Child, Preschool ,Karyotyping ,Tetrasomy ,Immunology ,Female - Abstract
Sex chromosome aneuploidies range in incidence from rather common to exceedingly rare and have a variable phenotype. We report 2 patients with sex chromosome aneuploidies who developed severe aplastic anemia requiring treatment. The first patient had tetrasomy X (48,XXXX) and presented at 9 years of age, and the second patient had trisomy X (47,XXX) and presented at 5 years of age. Although aplastic anemia has been associated with other chromosomal abnormalities, sex chromosome abnormalities have not been traditionally considered a risk factor for this condition. A review of the literature reveals that at least one other patient with a sex chromosome aneuploidy (45,X) has suffered from aplastic anemia and that other autosomal chromosomal anomalies have been described. Despite the uncommon nature of each condition, it is possible that the apparent association is coincidental. A better understanding of the genetic causes of aplastic anemia remains important.
- Published
- 2015
23. A unique case series of autosomal recessive bestrophinopathy exhibiting multigenerational inheritance
- Author
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Ahmed Sallam, M. Kathryn Williams, Sami H. Uwaydat, G. Bradley Schaefer, and Joshua S. Hardin
- Subjects
0301 basic medicine ,Adult ,Male ,Heterozygote ,genetic structures ,DNA Mutational Analysis ,Inheritance Patterns ,Genes, Recessive ,Consanguinity ,BEST1 gene ,urologic and male genital diseases ,03 medical and health sciences ,0302 clinical medicine ,Retinal Diseases ,Variable phenotype ,medicine ,Humans ,Genetic Testing ,Bestrophins ,Genetics (clinical) ,Genetic Association Studies ,Genetics ,Retina ,business.industry ,Bestrophinopathy ,Inheritance (genetic algorithm) ,Eye Diseases, Hereditary ,Middle Aged ,eye diseases ,Pedigree ,White (mutation) ,Ophthalmology ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,030221 ophthalmology & optometry ,Optometry ,Female ,sense organs ,business ,Autosomal recessive bestrophinopathy ,Tomography, Optical Coherence - Abstract
Autosomal recessive bestrophinopathy (ARB) is a retinal disease caused by biallelic mutations of the BEST1 gene. It has a variable phenotype with white flecks in the retina, multifocal yellow subretinal deposits, macular edema, choroidal neovascularization, hyperopia, and electrophysiological abnormalities. We describe a family with ARB and multigenerational inheritance.Three generations of a Middle Eastern family (a woman, one son, and two grandchildren) were evaluated by our ocular genetics team. Eye examinations, fundus photography, and optical coherence tomography (OCT) were performed. Genetic testing was obtained on examined patients and available relatives.The proband demonstrated counting fingers vision and white flecks in the retinal periphery, with macular subretinal fluid (SRF), loss of outer photoreceptor segments, and epiretinal membrane (ERM) on OCT. Two grandchildren demonstrated decreased vision, multifocal yellow subretinal deposits, and SRF on OCT. Two grandchildren examined elsewhere were reported to be similarly affected. A son's examination was normal except for extra-macular scars (from prior toxoplasmosis) and ERM. Genetic history revealed consanguinity and testing showed homozygosity for BEST1 mutations in the proband and two grandchildren c.473GA/c.473GA (R218H /R218H) and heterozygosity in two unaffected sons and two unaffected daughters-in-law c.473GA/WT (p.R218H/WT).We present a consanguineous family of five affected individuals with ARB and four confirmed carriers. Their pedigree was consistent with dominant inheritance and incomplete penetrance. Genetic testing clarified the diagnosis and mode of inheritance. We describe the genetic findings, phenotypic variability, and recessive inheritance of an often dominantly inherited mutation as notable elements in their case.
- Published
- 2017
24. Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome
- Author
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Amit M. Mathur, Shasha Bai, Chunqiao Luo, Dennis E. Mayock, Taeun Chang, Yvonne W. Wu, Raghu H. Ramakrishnaiah, Sandra E. Juul, Robert C. McKinstry, G. Bradley Schaefer, Krisa P. Van Meurs, and Sarah B. Mulkey
- Subjects
Male ,Time Factors ,Encephalopathy ,Neuroprotection ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,030225 pediatrics ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Erythropoietin ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Infant ,Magnetic resonance imaging ,Hypothermia ,medicine.disease ,Magnetic Resonance Imaging ,United States ,Neuroprotective Agents ,Treatment Outcome ,Anesthesia ,Brain Injuries ,Pediatrics, Perinatology and Child Health ,Hypoxia-Ischemia, Brain ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug ,Diffusion MRI - Abstract
In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. Trial registration ClinicalTrials.gov : NCT01913340 .
- Published
- 2016
25. Multi-Tiered Analysis of Brain Injury in Neonates With Congenital Heart Disease
- Author
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Raghu H. Ramakrishnaiah, Maria S. Melguizo, Charles M. Glasier, Michael L. Schmitz, Xiawei Ou, Adnan T. Bhutta, Sarah B. Mulkey, Christopher J. Swearingen, and G. Bradley Schaefer
- Subjects
Heart Defects, Congenital ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Heart disease ,Severity of Illness Index ,Article ,Risk Factors ,Internal medicine ,Severity of illness ,Prevalence ,medicine ,Humans ,cardiovascular diseases ,Cardiac Surgical Procedures ,Intraparenchymal hemorrhage ,Retrospective Studies ,Brain Diseases ,Arkansas ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Brain ,Magnetic resonance imaging ,Retrospective cohort study ,Vascular surgery ,Prognosis ,medicine.disease ,Magnetic Resonance Imaging ,Cardiac surgery ,Pediatrics, Perinatology and Child Health ,Cardiology ,Apgar score ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Early brain injury occurs in newborns with congenital heart disease (CHD) placing them at risk for impaired neurodevelopmental outcomes. Predictors for preoperative brain injury have not been well described in CHD newborns. This study aimed to analyze, retrospectively, brain magnetic resonance imaging (MRI) in a heterogeneous group of newborns who had CHD surgery during the first month of life using a detailed qualitative CHD MRI Injury Score, quantitative imaging assessments (regional apparent diffusion coefficient [ADC] values and brain volumes), and clinical characteristics. Seventy-three newborns that had CHD surgery at 8 ± 5 (mean ± standard deviation) days of life and preoperative brain MRI were included; 38 also had postoperative MRI. Thirty-four (34/73, 47%) had at least 1 type of preoperative brain injury, and 28/38 (74%) had postoperative brain injury. The 5-minute APGAR score was negatively associated with preoperative injury, but there was no difference between CHD types. Infants with intraparenchymal hemorrhage, deep gray matter injury, and/or watershed infarcts had the highest CHD MRI Injury Scores. ADC values and brain volumes were not different in infants with different CHD types, or in those with and without brain injury. In a mixed group of CHD newborns, brain injury was found preoperatively on MRI in almost 50%, and there were no significant baseline characteristic differences to predict this early brain injury, except 5-minute APGAR score. We conclude that all infants, regardless of CHD type, who require early surgery, should be evaluated with MRI as they are all at high risk for brain injury.
- Published
- 2013
26. In memory of Murray Feingold (1930-2015)
- Author
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Ann Haskins Olney, Catherine Nowak, and G. Bradley Schaefer
- Subjects
World Wide Web ,Computer science ,Genetics, Medical ,Genetics ,Portraits as Topic ,History, 20th Century ,History, 21st Century ,Genetics (clinical) ,United States - Published
- 2016
27. Genetics and Hearing Loss
- Author
-
G. Bradley Schaefer
- Subjects
medicine.medical_specialty ,Hearing loss ,business.industry ,otorhinolaryngologic diseases ,medicine ,food and beverages ,Early detection ,medicine.symptom ,Audiology ,business ,Hearing screening - Abstract
The primary goal of infant hearing screening is, of course, the improved outcome of speech and language in those identified early. There is, however, another major advantage in the early detection of hearing loss. Hearing loss identified by newborn screening can prompt an early investigation into the etiology of the loss. Most cases of hearing loss detected by newborn screening have a genetic etiology. A genetics evaluation can provide the family and providers with several critical pieces of information. For many families, simply knowing the “why” is an important question. Identifying an etiology can also answer questions about recurrence risks for the immediate and extended family. In addition, many of the causes of childhood hearing loss have associated medical conditions, some of which can be medically serious. Knowledge of these risk factors can lead to interventions that prevent morbidity and mortality. All health care providers who work with children with a hearing loss should be aware of the details of a genetic evaluation. They should be prepared to share with the family information regarding the process, the diagnostic yield, and the risks and benefits of such an evaluation.
- Published
- 2012
28. Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes
- Author
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Jill A, Rosenfeld, Ryan N, Traylor, G Bradley, Schaefer, Elizabeth W, McPherson, Blake C, Ballif, Eva, Klopocki, Stefan, Mundlos, Lisa G, Shaffer, Arthur S, Aylsworth, and William G, Wilson
- Subjects
Male ,Proband ,Adolescent ,DNA Copy Number Variations ,Population ,Inheritance Patterns ,Biology ,Article ,Chromosome Duplication ,Gene duplication ,Genetics ,medicine ,Congenital Bone Marrow Failure Syndromes ,Humans ,Genetic Testing ,Upper Extremity Deformities, Congenital ,Copy-number variation ,Child ,education ,Genetics (clinical) ,Segmental duplication ,Gene Rearrangement ,Comparative Genomic Hybridization ,education.field_of_study ,TAR syndrome ,Infant, Newborn ,Infant ,Gene rearrangement ,medicine.disease ,Thrombocytopenia ,Pedigree ,Radius ,Phenotype ,Chromosomes, Human, Pair 1 ,Child, Preschool ,Female ,Chromosome Deletion ,Comparative genomic hybridization - Abstract
Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a ‘partial' TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. Otherwise, phenotypic features varied among individuals with these microdeletions and microduplications. The recurrent, proximal 1q21.1 microduplications are enriched in our population undergoing genetic testing compared with control populations. Therefore, CNVs in proximal 1q21.1 can be a contributing factor for the development of abnormal phenotypes in some carriers.
- Published
- 2012
29. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations
- Author
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Cynthia J. Curry, Margarita Raygada, Raoul C.M. Hennekam, Virginia Kimonis, John M. Graham, Alexa Kidd, David J. Amor, Helen Murphy, Annmarie Sommer, Salim Aftimos, Maureen Bocian, Amy Shealy, Michael T. Gabbett, Graeme C.M. Black, Susan Tomkins, Lakshmi Mehta, Bernhard Zabel, Michael Field, Joyce T. Turner, Margot I. Van Allen, Mark J. Stephan, Wendy E. Smith, Sally Ann Lynch, David Tilstra, Janice Zunich, Anne Chun Hui Tsai, Alan F. Rope, Pradeep Vasudevan, Kenneth N. Rosenbaum, Robert J. Hopkin, Julie C. Sapp, Moran Gal, Kyrieckos A. Aleck, Hülya Kayserili, Jennifer J. Johnston, Angela E. Lin, Julie McGaughran, Leslie G. Biesecker, G. Bradley Schaefer, Ruth Day, Joann Bodurtha, Ikuma Fujiwara, Heather J. Stalker, Dian Donnai, Melissa K. Maisenbacher, Peter Hedera, Maria Soller, Sahar Mansour, Nathaniel H. Robin, Joseph H. Hersh, Pamela Trapane, Gerald F. Cox, Bernhard Steiner, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatrics
- Subjects
Proband ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Genotype ,Kruppel-Like Transcription Factors ,Nerve Tissue Proteins ,Biology ,medicine.disease_cause ,Craniofacial Abnormalities ,Zinc Finger Protein Gli3 ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Genetics (clinical) ,Greig cephalopolysyndactyly syndrome ,Mutation ,Polydactyly ,Pallister-Hall Syndrome ,fungi ,medicine.disease ,Acrocallosal syndrome ,Phenotype ,Pallister–Hall syndrome ,Medical genetics ,Syndactyly ,Mouth Abnormalities - Abstract
A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial- digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. Hum Mutat 31:1142-1154, 2010. (C) 2010 Wiley-Liss, Inc
- Published
- 2010
30. Genetics Considerations in Cerebral Palsy
- Author
-
G. Bradley Schaefer
- Subjects
Genetic heterogeneity ,Cerebral Palsy ,Inheritance (genetic algorithm) ,medicine.disease ,Motor function ,Cerebral palsy ,Pediatrics, Perinatology and Child Health ,medicine ,Etiology ,Humans ,Multifactorial Inheritance ,Neurology (clinical) ,Child ,Psychology ,Neuroscience - Abstract
Cerebral palsy refers to a collective of neurologic conditions that share in common disorders of motor function and posture. Traditionally, and still today in many circles, the term is considered almost synonymous with brain injury. Multiple lines of evidence, however, point to the fact that cerebral palsy is rarely caused by problems with perinatal management. In fact, a mounting body of evidence points to strong genetic influences on the occurrence of cerebral palsy. Like most neurogenetic conditions, cerebral palsy exhibits complex inheritance. The best descriptor of the inheritance of cerebral palsy would be that of "multifactorial inheritance." This implies etiologic and genetic heterogeneity with complex interactions with multiple environmental influences. This article reviews known genetic influences on the origin of cerebral palsy. A proposed scheme for the genetic evaluation in identifying the etiology of cerebral palsy is provided.
- Published
- 2008
31. Knowledge and Beliefs About Genetics and Smoking Among Visitors and Staff at a Health Care Facility
- Author
-
Gwendolyn M. Reiser, Jan R. Atwood, Rhonda M. Wolfe, Julia F. Houfek, Stephen I. Rennard, G. Bradley Schaefer, and Sangeeta Agrawal
- Subjects
Adult ,Male ,Health Knowledge, Attitudes, Practice ,medicine.medical_specialty ,Smoking Prevention ,Health Promotion ,Logistic regression ,medicine.disease_cause ,Midwestern United States ,Nursing care ,Health care ,Heredity ,Genetic predisposition ,medicine ,Humans ,Genetic Predisposition to Disease ,General Nursing ,Aged ,Aged, 80 and over ,Genetics ,business.industry ,Public health ,Smoking ,Public Health, Environmental and Occupational Health ,Middle Aged ,Former Smoker ,Logistic Models ,Socioeconomic Factors ,Female ,Baccalaureate Degree ,business - Abstract
Objectives: The primary purpose of this study was to describe individuals' knowledge and beliefs about genetics and smoking. Secondary purposes were to describe (a) differences in knowledge and beliefs based on smoking status, gender, and education and (b) relationships among perceived genetic predisposition for smoking, background characteristics, and knowledge and beliefs about genetics and smoking. Because genetics influences smoking, genetic information will likely be used to individualize future cessation treatment. Design: Questionnaire data were collected about knowledge and beliefs about genetics and smoking, smoking history, and demographics from visitors and staff at a nursing care facility. Data were analyzed with bivariate statistics and logistic regression. Sample: Participants (N=92), ages 19–82, were classified by smoking status. Results: Participants had little knowledge about genetics and smoking or mechanisms of heredity. Most did not believe that genetics caused smoking or influenced cessation. Predictors of perceived genetic predisposition for smoking were smoking status (current/former smoker), education (
- Published
- 2008
32. Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders
- Author
-
Richard E. Lutz and G. Bradley Schaefer
- Subjects
Male ,medicine.medical_specialty ,Yield (finance) ,MEDLINE ,Recurrence risk ,Clinical Protocols ,medicine ,Clinical genetic ,Humans ,In patient ,Autistic Disorder ,Diagnostic Errors ,Medical diagnosis ,Child ,Psychiatry ,Intensive care medicine ,Genetics (clinical) ,Retrospective Studies ,Chromosome Aberrations ,business.industry ,Genetic Diseases, Inborn ,Retrospective cohort study ,medicine.disease ,Autism ,Female ,business ,Metabolism, Inborn Errors - Abstract
Purpose: Clinical geneticists are often asked to evaluate patients with autism spectrum disorders (ASDs) in reference to questions about cause and recurrence risk. Recent advances in diagnostic testing technology have greatly increased the options available to them. It is not currently clear what the overall diagnostic yield of a battery of tests, either collectively or individually, might be. The purpose of this study was to evaluate the diagnostic yield of a stepwise approach we have implemented in our clinics. Methods: We used a three-tiered neurogenetic evaluation scheme designed to determine the cause of ASDs in patients referred for clinical genetic consultation. We reviewed the results of our diagnostic evaluations on all patients referred with a confirmed diagnosis of autism over a 3-year period. Results: By using this approach, we found an overall diagnostic yield for ASDs of more than 40%. This represents a significant increase in the diagnostic yield reported just a few years ago. Conclusions: Given the implications of these diagnoses on recurrence risk and associated medical conditions, a targeted neurogenetic evaluation of all persons with ASDs seems warranted. We discuss the issues in the future implementation of a fourth tier to the evaluation with the potential for an even higher diagnostic yield.
- Published
- 2006
33. A Tribute to Henry H. Turner, MD (1892???1970)
- Author
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G Bradley Schaefer and Harris D. Riley
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,Art history ,Medicine ,Tribute ,business - Published
- 2004
34. Windows Into the Mind
- Author
-
G. Bradley Schaefer and Kathy Coufal
- Subjects
World Wide Web ,Speech and Hearing ,Computer science - Published
- 2003
35. Radioulnar Synostosis and Brain Abnormalities in a Patient With 17q21.31 Microdeletion Involving EFTUD2
- Author
-
Yuri A. Zarate, G. Bradley Schaefer, and Carla Bell
- Subjects
medicine.medical_specialty ,Microcephaly ,Toe syndactyly ,medicine ,Humans ,Abnormalities, Multiple ,Craniofacial ,Ribonucleoprotein, U5 Small Nuclear ,Sequence Deletion ,business.industry ,Overlapping toe ,Infant, Newborn ,Brain ,Anatomy ,Mandibulofacial dysostosis ,medicine.disease ,Dysostoses ,Microarray Analysis ,Peptide Elongation Factors ,Surgery ,Phenotype ,Otorhinolaryngology ,Radioulnar synostosis ,Female ,Oral Surgery ,Haploinsufficiency ,business ,Mandibulofacial Dysostosis ,Chromosomes, Human, Pair 17 - Abstract
Mandibulofacial dysostosis with microcephaly is a rare syndromic craniofacial condition caused by heterozygous loss-of-function mutations of the EFTUD2 gene on 17q21.31. Thus far, the described musculoskeletal findings in patients with this condition include proximally placed or duplicated thumbs, overlapping toes, and toe syndactyly. We describe a severe case of a patient with a 17q21.31 microdeletion and many of the phenotypic features described in mandibulofacial dysostosis with microcephaly who had bilateral proximal radioulnar synostosis and brain abnormalities. This provides further evidence of the clinical overlap among mandibulofacial and acrofacial dysostoses syndromes and expands the phenotype of EFTUD2 haploinsufficiency due to larger deletions.
- Published
- 2014
36. Recombinant human acid ??-glucosidase enzyme therapy for infantile glycogen storage disease type II: Results of a phase I/II clinical trial
- Author
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Andrea Amalfitano, A. Resai Bengur, Richard P. Morse, Joseph M. Majure, Laura E. Case, Deborah L. Veerling, Joanne Mackey, Priya Kishnani, Wendy Smith, Alison McVie-Wylie, Jennifer A. Sullivan, George E. Hoganson, John A. Phillips, G. Bradley Schaefer, Joel Charrow, Russell E. Ware, Edward H. Bossen, and Yuan-Tsong Chen
- Subjects
Genetics (clinical) - Published
- 2001
37. Recombinant human acid α-glucosidase enzyme therapy for infantile glycogen storage disease type II: Results of a phase I/II clinical trial
- Author
-
Yuan-Tsong Chen, A.Resai Bengur, John Phillips, Russell E. Ware, Andrea Amalfitano, Joanne Mackey, Joseph M. Majure, Richard P. Morse, Wendy A. Smith, Edward H. Bossen, Priya S. Kishnani, Jennifer A. Sullivan, George E. Hoganson, Alison McVie-Wylie, G. Bradley Schaefer, Deborah L. Veerling, Joel Charrow, and Laura E. Case
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Skeletal muscle ,Enzyme replacement therapy ,Biology ,Muscle disorder ,medicine.disease ,Molecular biology ,Gastroenterology ,medicine.anatomical_structure ,Internal medicine ,Glycogen storage disease type II ,Acid alpha-glucosidase ,medicine ,Adverse effect ,Alglucosidase alfa ,Genetics (clinical) ,medicine.drug - Abstract
Purpose: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid α-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. Methods: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure–free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. Results: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. Conclusions: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.
- Published
- 2001
38. Identification of an X-Linked Deletion Syndrome Through Comparative Genomic Hybridization Microarray
- Author
-
Eric T. Rush and G. Bradley Schaefer
- Subjects
Male ,Adolescent ,Microarray ,Hearing loss ,Developmental Disabilities ,Biology ,Connexins ,Choroideremia ,medicine ,Humans ,Abnormalities, Multiple ,Deletion syndrome ,Hearing Loss ,Gene ,Sequence Deletion ,Genetics ,Comparative Genomic Hybridization ,Glucose Transporter Type 4 ,Brain ,Genetic Diseases, X-Linked ,medicine.disease ,Magnetic Resonance Imaging ,Xq28 ,Connexin 26 ,Mutation ,Pediatrics, Perinatology and Child Health ,Identification (biology) ,Neurology (clinical) ,medicine.symptom ,Comparative genomic hybridization - Abstract
We present a single case of a young man with multiple congenital anomalies. For years, a unifying diagnosis could not be made. As his case developed, more clues came to light, but still no recognizable pattern could be identified. Ultimately, the combination of orofacial clefting, neurosensory hearing loss, choroideremia, and cognitive delays were shown to be due to an Xq21 [corrected] micro-deletion as seen on comparative genomic hybridizations studies. A review of the genes contained in this region clearly explain his constellation of findings.
- Published
- 2010
39. Bilateral familial nevus of Ota
- Author
-
Sami H. Uwaydat, G. Bradley Schaefer, Sunali Goyal, and Paul H. Phillips
- Subjects
Male ,medicine.medical_specialty ,Skin Neoplasms ,business.industry ,Eye Neoplasms ,Siblings ,Glaucoma ,Sister ,medicine.disease ,Nevus of Ota ,Dermatology ,eye diseases ,Melanocytic lesion ,Scleral Diseases ,Ophthalmology ,Increased risk ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Female ,skin and connective tissue diseases ,business ,Child - Abstract
Nevus of Ota is a benign congenital melanocytic lesion found most commonly in people of Asian ancestry. It is associated with an increased risk of glaucoma and uveal melanomas. Most cases are sporadic and unilateral. We present the first reported case of a brother and sister with familial, bilateral nevus of Ota.
- Published
- 2013
40. Persistent congenital hyperinsulinism in two patients with Beckwith-Wiedemann syndrome due to mosaic uniparental disomy 11p
- Author
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Jose Bernardo Quintos, Andrew Robin, Yuri A. Zarate, Natasha Shur, Adolfo D. Garnica, and G. Bradley Schaefer
- Subjects
Male ,medicine.medical_specialty ,Beckwith-Wiedemann Syndrome ,Endocrinology, Diabetes and Metabolism ,Beckwith–Wiedemann syndrome ,Octreotide ,Hypoglycemia ,Gastroenterology ,Endocrinology ,Internal medicine ,medicine ,Humans ,medicine.diagnostic_test ,business.industry ,Mosaicism ,Infant, Newborn ,Infant ,Uniparental Disomy ,medicine.disease ,Uniparental disomy ,Pediatrics, Perinatology and Child Health ,Skin biopsy ,Congenital hyperinsulinism ,Congenital Hyperinsulinism ,business ,Hyperinsulinism ,medicine.drug ,SNP array - Abstract
Congenital hyperinsulinism (CHI) is a rare metabolic disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. We describe the clinical presentation and management of congenital hyperinsulinism and persistent hypoglycemia in two infants. Both patients had an initial clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) but normal methylation analysis for LIT1 and H19 status. Both patients were eventually found to have mosaic uniparental disomy 11p diagnosed by single nucleotide polymorphism (SNP) array in DNA isolated from lymphoblasts and fibroblasts, respectively. We report that patients with mosaic BWS are at increased risk for both transient and refractory hypoglycemia that may need aggressive management with diazoxide, octreotide, high glucose infusion rates, and a frequent feeding regime. Our patient experience supports the case for pursuing further testing in patients with features of BWS with normal methylation studies, karyotype, and SNP arrays on blood. The next logical step is SNP array on skin biopsy to rule out mosaicism.
- Published
- 2013
41. Practical Applications of Telemedicine for Pediatricians
- Author
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Neil E. Herendeen and G. Bradley Schaefer
- Subjects
Telemedicine ,Nursing ,business.industry ,Pediatrics, Perinatology and Child Health ,Humans ,Medically Underserved Area ,Medicine ,Medical emergency ,business ,medicine.disease ,Pediatrics ,Health Services Accessibility - Abstract
Advances in technology and telecommunications have opened the door for primary care pediatricians to provide a range of medical services that extend the walls of their medical home. Constraints of time, distance, and access can be overcome with electronic transmission of medical information that provide patients care when and where they need it by providers they know and trust. No longer are on-call pediatricians staying home tied to their land-line telephone, assessing acute conditions based only on parent descriptions and documenting the conversation on paper call slips. If this sounds like you, please read this article for a 2009 alternative.
- Published
- 2009
42. Hypothalamic dysfunction with polydactyly and hypoplastic nails
- Author
-
Ann Haskins Olney, John B. Bodensteiner, and G. Bradley Schaefer
- Subjects
Male ,Postaxial polydactyly ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pediatrics ,Conservative management ,Hamartoma ,Genetic counseling ,Hypothalamus ,Nails, Malformed ,Hypothalamic hamartoma ,medicine ,Humans ,Intrafamilial variability ,Brain Diseases ,Polydactyly ,business.industry ,Infant, Newborn ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,Hypoplastic nails ,Child, Preschool ,Hypothalamic dysfunction ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,business - Abstract
Attention to a careful diagnostic work-up should be given to patients with postaxial polydactyly or apparently isolated hypothalamic hamartomas. Early recognition of the condition is critical for management, particularly for anticipating and preventing endocrine emergencies. Conservative management of the hypothalamic hamartoma should be stressed. Finally, detailed genetic counseling should be provided to the family regarding autosomal-dominant inheritance as well as the wide range of interfamilial and intrafamilial variability.
- Published
- 1999
43. Matrix metalloproteinases and their inhibitors in tumor invasion and metastasis
- Author
-
G. Bradley Schaefer, Bruce A. Beuhler, Velidi H. Rao, Rakesh K. Singh, Warren G. Sanger, Richard H. Finnell, and Bhavana J. Dave
- Subjects
Therapeutic approach ,business.industry ,Tumor Cell Invasion ,Metastatic phenotype ,Cancer research ,medicine ,Nanotechnology ,General Chemistry ,Matrix metalloproteinase ,medicine.disease ,business ,Metastasis - Abstract
The recent progress in matrix metalloproteinases (MMPs) research has opened up many cellular targets in a variety of diseases. We have discussed some of the interesting and newly described roles of MMPs in modulating metastatic phenotype in malignancies. This information suggests a more specific and exclusive role of MMPs as important regulators of tumor cell invasion and metastasis. A great deal of room exists for redefining our current understanding of the MMPs system; the more we understand about how MMPs act, the better we will understand the pathobiology of metastasis. Research in the regulation of MMPs and the potential use of MMPs for therapeutic interventions in metastasis continues to expand. The future of therapy involving inhibitors of MMPs as a part of the armamentarium against human neoplasm should be viewed with cautious optimism. This therapeutic approach is beginning to find a place in our understanding of metastatic tumors, but with perhaps few exceptions should still be considered experimental. This area of research now needs more biological knowledge and imagination on the part of investigators to make future achievements possible.
- Published
- 1999
44. Case Report: Two Patients With Oculocerebrocutaneous Syndrome and Terminal Digital Amputations
- Author
-
Nathan G. Asher, G. Bradley Schaefer, and Ann Haskins Olney
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,business.industry ,Infant, Newborn ,Brain ,Infant ,Syndrome ,Oculocerebrocutaneous syndrome ,medicine.disease ,Surgery ,Fingers ,Terminal (electronics) ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Abnormalities, Multiple ,Female ,Eye Abnormalities ,Neurology (clinical) ,business - Abstract
We report 2 cases of patients with a rare multiple anomaly condition reported as Dellman (oculocerebrocutaneous) syndrome. In this article we discuss the clinical features and genetics of this condition. Notably, both of these patients have digital abnormalities which have not been previously described in the literature.
- Published
- 2008
45. Identical twins discordant for Sotos syndrome
- Author
-
W. Ted Brown, C. M. Miezejeski, John A. Tsiouris, Maryellen Keogh, G. Bradley Schaefer, Vicki Sudhalter, and Krystina E. Wisniewski
- Subjects
Environmental effect ,Genetics ,Sotos syndrome ,medicine ,Monozygotic twin ,Congenital disease ,Biology ,medicine.disease ,Identical twins ,Genetics (clinical) ,Genetic determinism ,Uniparental disomy ,Epigenetic Change - Abstract
The cause of Sotos syndrome is unknown but it usually occurs sporadically. Recent studies have shown no evidence of uniparental disomy. One set of concordant monozygotic twins has been reported. We have identified the Sotos syndrome in one of two 5-year-old male monozygotic twins. Our finding of discordance in these identical twins suggests that a postconceptual mutation, or epigenetic change and/or an environmental factor may be involved in the cause of Sotos syndrome.
- Published
- 1998
46. Does selection bias determine the prevalence of the cavum septi pellucidi?
- Author
-
G. Bradley Schaefer, Kelli J Pauling, John B. Bodensteiner, and Jeffery P. Hogg
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Developmental Disabilities ,Central nervous system disease ,Developmental Neuroscience ,Neuroimaging ,Intellectual Disability ,Epidemiology ,Intellectual disability ,Prevalence ,medicine ,Humans ,Child ,Selection Bias ,Septum pellucidum ,Aged ,Retrospective Studies ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Infant ,Magnetic resonance imaging ,Retrospective cohort study ,Middle Aged ,West Virginia ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,Neurology ,El Niño ,Child, Preschool ,Population Surveillance ,Pediatrics, Perinatology and Child Health ,Female ,Septum Pellucidum ,Neurology (clinical) ,Nervous System Diseases ,business - Abstract
This study was undertaken to ascertain the prevalence of the persistent cavum septi pellucidi in children and adults by magnetic resonance imaging (MRI) and to compare the clinical indications for neuroimaging in the two age groups as a measure of group selection bias. All scans performed at West Virginia University during 1997 were reviewed for the presence of a persistent cavum septi pellucidi. The clinical indications for the MRI study were determined in 100 consecutive adult (17 years of age or older) and 100 consecutive pediatric (younger than 17 years of age) scans. In the 203 pediatric patients the prevalence of a persistent cavum septi pellucidi was 6.9%, and in the 814 adults the prevalence was 2.1%. Mental retardation/developmental delay was the clinical indication for at least 26% of the pediatric patients but was not an indication for neuroimaging in the adult study group. The known association of persistent cavum septi pellucidi with mental retardation and in several groups of patients with conditions clinically characterized by mental dysfunction suggests that the higher prevalence in the pediatric study group may primarily be the result of the patient selection bias operating through the different clinical indications for neuroimaging in the two populations.
- Published
- 1998
47. Volumetric neuroimaging in Usher syndrome: Evidence of global involvement
- Author
-
Jennifer M. Craft, James N. Thompson, G. Bradley Schaefer, John B. Bodensteiner, and William J. Kimberling
- Subjects
Pathology ,medicine.medical_specialty ,Cerebellum ,business.industry ,Hearing loss ,Usher syndrome ,Encephalopathy ,medicine.disease ,Atrophy ,medicine.anatomical_structure ,Neuroimaging ,otorhinolaryngologic diseases ,Cerebellar vermis ,Medicine ,Sensorineural hearing loss ,medicine.symptom ,business ,Genetics (clinical) - Abstract
Usher syndrome is a group of genetic disorders consisting of congenital sensorineural hearing loss and retinitis pigmentosa of variable onset and severity depending on the genetic type. It was suggested that the psychosis of Usher syndrome might be secondary to a metabolic degeneration involving the brain more diffusely. There have been reports of focal and diffuse atrophic changes in the supratentorial brain as well as atrophy of some of the structures of the posterior fossa. We previously performed quantitative analysis of magnetic resonance imaging studies of 19 Usher syndrome patients (12 with type I and 7 with type II) looking at the cerebellum and various cerebellar components. We found atrophy of the cerebellum in both types and sparing of cerebellar vermis lobules I-V in type II Usher syndrome patients only. We now have studied another group of 19 patients (with some overlap in the patients studied from the previous report) with Usher syndrome (8 with type I, 11 with type II). We performed quantitative volumetric measurements of various brain structures compared to age- and sex-matched controls. We found a significant decrease in intracranial volume and in size of the brain and cerebellum with a trend toward an increase in the size of the subarachnoid spaces. These data suggest that the disease process in Usher syndrome involves the entire brain and is not limited to the posterior fossa or auditory and visual systems.
- Published
- 1998
48. Evaluation of mental retardation: Recommendations of a consensus conference
- Author
-
Christopher Cunniff, John Opitz, John B. Moeschler, Jack Tarleton, Marilyn C. Jones, Suzanne B. Cassidy, John C. Carey, Janice L. B. Byrne, G. Bradley Schaefer, John M. Graham, Roger E. Stevenson, David J. Aughton, Cynthia J. Curry, Michael M. Kaback, and Stuart Schwartz
- Subjects
Microcephaly ,medicine.medical_specialty ,business.industry ,Macrocephaly ,medicine.disease ,Fragile X syndrome ,Developmental disorder ,Neuroimaging ,medicine ,Etiology ,Medical genetics ,Family history ,medicine.symptom ,business ,Genetics (clinical) ,Clinical psychology - Abstract
A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.
- Published
- 1997
49. The neuroimaging findings in Sotos syndrome
- Author
-
G. Bradley Schaefer, John B. Bodensteiner, Bruce A. Buehler, Angela Lin, and Trevor R. P. Cole
- Subjects
medicine.medical_specialty ,Periventricular leukomalacia ,Sotos syndrome ,business.industry ,Macrocephaly ,Gray matter heterotopias ,medicine.disease ,Corpus callosum ,medicine.anatomical_structure ,Neuroimaging ,medicine ,Radiology ,medicine.symptom ,business ,Cavum septum pellucidum ,Genetics (clinical) ,Ventriculomegaly - Abstract
We reviewed the neuroimaging studies of 40 patients with classic Sotos syndrome. The studies consisted of CT scans only in 4 patients and one or more MRI scans in 36 patients. The diagnosis of Sotos syndrome was made using well-established clinical criteria. The neuroimaging studies of each patient were evaluated subjectively by visual inspection and the chief findings were tabulated and grouped into five categories: 1) ventricular abnormalities, 2) extracerebral fluid spaces, 3) midline abnormalities, 4) migrational abnormalities, and 5) others. The most common abnormality of the cerebral ventricles was prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). The supratentorial extracerebral fluid spaces were increased for age in 70% of the patients and the fluid spaces in the posterior fossa were increased in 70% also. A variety of midline abnormalities were noted but anomalies of the corpus callosum were almost universal. Gray matter heterotopias occurred in only 3 (8%) of 36 patients. Periventricular leukomalacia, presumably the result of prenatal or perinatal difficulties and unrelated to the basic condition, was the most common of the miscellaneous other abnormalities noted. The neuroimaging findings of Sotos syndrome are distinct enough to allow differentiation of this syndrome from other mental retardation syndromes with macrocephaly.
- Published
- 1997
50. [Untitled]
- Author
-
Bruce A. Buehler, Julia A. Bridged, Jasti S. Rao, Duane C. Delimont, Warren G. Sanger, G. Bradley Schaefer, Rakesh K. Singh, Raymond Sawaya, Garth L. Nicolson, James R. Neff, Christopher M. Dunn, and Velidi H. Rao
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Cellular differentiation ,General Medicine ,Matrix metalloproteinase ,Biology ,medicine.disease ,Molecular biology ,In vitro ,Oncology ,Giant cell ,Cancer cell ,Collagenase ,medicine ,medicine.drug ,Giant-cell tumor of bone - Abstract
Matrix metalloproteinases (MMPs) play an important regulatory role in tissue morphogenesis, cell differentiation, tumor invasion and metastasis. Several authors have reported a direct correlation between the production of 72 kDa (MMP-2) and 92 kDa (MMP-9) type IV collagenases/gelatinases and the metastatic potential of cancer cells. Recently, we have identified the expression of both MMP-2 and MMP-9 in primary cultures of human giant cell tumor (GCT) of bone in vitro, and in tissue extracts in vivo. Interestingly, MMP-9 is not secreted by late-passaged GCT cells. It is possible that the production of MMP-9 is regulated by certain factor(s) secreted by the multinucleated giant cells in the primary culture. In order to test this hypothesis, the effect of primary-culture-conditioned medium on the expression of MMP-9 by late-passaged mononuclear stromal cells was examined. Adding conditioned medium from the primary GCT culture to the late-passaged stromal cells induced MMP-9, as evidenced by the presence of lytic bands at Mr 92000 and 72000 on a gelatin zymogram. These enzyme activities were inhibited by EDTA, a well-known inhibitor of the MMPs. We confirmed these results by Western blotting using specific antibodies and RT-PCR for MMP-2 and MMP-9. Immunofluorescence studies with specific antibodies to MMP-9 further confirmed its expression by the passaged stromal cells cultured in the primary-culture-conditioned medium. The data indicate that MMP-2 and MMP-9 are produced by the mononuclear stromal cells when cultured in GCT primary-culture-conditioned medium. This suggests that multinucleated giant cells in primary cultures secrete a factor(s) that stimulates stromal cells to produce MMP-9, which, in turn, may contribute to the aggressive behavior of GCT.
- Published
- 1997
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