141 results on '"G. Bradley Schaefer"'
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2. 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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Medicine ,Genetics ,QH426-470 - Abstract
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
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3. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
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Michael A. Levy, David B. Beck, Kay Metcalfe, Sofia Douzgou, Sivagamy Sithambaram, Trudie Cottrell, Muhammad Ansar, Jennifer Kerkhof, Cyril Mignot, Marie-Christine Nougues, Boris Keren, Hannah W. Moore, Renske Oegema, Jacques C. Giltay, Marleen Simon, Richard H. van Jaarsveld, Jessica Bos, Mieke van Haelst, M. Mahdi Motazacker, Elles M. J. Boon, Gijs W. E. Santen, Claudia A. L. Ruivenkamp, Marielle Alders, Teresa Romeo Luperchio, Leandros Boukas, Keri Ramsey, Vinodh Narayanan, G. Bradley Schaefer, Roberto Bonasio, Kimberly F. Doheny, Roger E. Stevenson, Sidharth Banka, Bekim Sadikovic, and Jill A. Fahrner
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.
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- 2021
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4. Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
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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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SCN8A ,sodium channel ,epilepsy ,seizure ,mouse ,mutation ,Therapeutics. Pharmacology ,RM1-950 - 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
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5. Author Correction: Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
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Michael A. Levy, David B. Beck, Kay Metcalfe, Sofia Douzgou, Sivagamy Sithambaram, Trudie Cottrell, Muhammad Ansar, Jennifer Kerkhof, Cyril Mignot, Marie-Christine Nougues, Boris Keren, Hannah W. Moore, Renske Oegema, Jacques C. Giltay, Marleen Simon, Richard H. van Jaarsveld, Jessica Bos, Mieke van Haelst, M. Mahdi Motazacker, Elles M. J. Boon, Gijs W. E. Santen, Claudia A. L. Ruivenkamp, Marielle Alders, Teresa Romeo Luperchio, Leandros Boukas, Keri Ramsey, Vinodh Narayanan, G. Bradley Schaefer, Roberto Bonasio, Kimberly F. Doheny, Roger E. Stevenson, Siddharth Banka, Bekim Sadikovic, and Jill A. Fahrner
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Medicine ,Genetics ,QH426-470 - Published
- 2021
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6. Correction: G. Bradley Schaefer. Clinical Genetic Aspects of ASD Spectrum Disorders. Int. J. Mol. Sci. 2016, 17, 180
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G. Bradley Schaefer
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n/a ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The author wishes to make a change to the published paper [1].[...]
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- 2016
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7. Clinical Genetic Aspects of ASD Spectrum Disorders
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G. Bradley Schaefer
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multifactorial inheritance ,genetic testing ,diagnostic yield ,copy number variants ,gene sequencing ,genomics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Early presumptions opined that autism spectrum disorder (ASD) was related to the rearing of these children by emotionally-distant mothers. Advances in the 1960s and 1970s clearly demonstrated the biologic basis of autism with a high heritability. Recent advances have demonstrated that specific etiologic factors in autism spectrum disorders can be identified in 30%–40% of cases. Based on early reports newer, emerging genomic technologies are likely to increase this diagnostic yield to over 50%. To date these investigations have focused on etiologic factors that are largely mono-factorial. The currently undiagnosed causes of ASDs will likely be found to have causes that are more complex. Epigenetic, multiple interacting loci, and four dimensional causes (with timing as a variable) are likely to be associated with the currently unidentifiable cases. Today, the “Why” is more important than ever. Understanding the causes of ASDs help inform families of important issues such as recurrence risk, prognosis, natural history, and predicting associated co-morbid medical conditions. In the current era of emerging efforts in “personalized medicine”, identifying an etiology will be critical in identifying endo-phenotypic groups and individual variations that will allow for tailored treatment for persons with ASD.
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- 2016
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8. 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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- 2022
9. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
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Trudie Cottrell, Jacques C. Giltay, Richard H. van Jaarsveld, Elles M. J. Boon, Roger E. Stevenson, Michael A. Levy, Kimberly F. Doheny, Bekim Sadikovic, G. Bradley Schaefer, Roberto Bonasio, Muhammad Ansar, Vinodh Narayanan, Mieke M. van Haelst, Jill A. Fahrner, Marleen Simon, David B. Beck, Claudia A. L. Ruivenkamp, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marie-Christine Nougues, Hannah W. Moore, Marielle Alders, Renske Oegema, M. Mahdi Motazacker, Kay Metcalfe, Cyril Mignot, Jennifer Kerkhof, Gijs W. E. Santen, Jessica Bos, Sofia Douzgou, Siddharth Banka, Keri Ramsey, Boris Keren, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ANS - Complex Trait Genetics, AR&D - Amsterdam Reproduction & Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
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Genetics ,Epigenomics ,DNA methylation ,Neurodevelopmental disorders ,Diagnostic markers ,QH426-470 ,Biology ,medicine.disease ,Phenotype ,Genome ,Article ,Neurodevelopmental disorder ,DNA demethylation ,CpG site ,medicine ,DNMT1 ,Medicine ,Epigenetics ,Author Correction ,Molecular Biology ,Genetics (clinical) - Abstract
TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.
- Published
- 2021
10. 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
11. The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study
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B Robert Peters, Peina Wu, Ryan K Thorpe, Kenny H. Chan, Richard J.H. Smith, Qiuju Wang, G. Bradley Schaefer, Yoel Hirsch, Pu Dai, Lei Xu, Tao Yang, Huijun Yuan, Nathaniel H. Robin, Krista Sondergaard Schatz, Joann Bodurtha, Hela Azaiez, and Zuhair Abdalla Rahbeeni
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medicine.medical_specialty ,Absolute threshold of hearing ,medicine.diagnostic_test ,Hearing loss ,Auditory neuropathy ,Membrane Proteins ,Audiogram ,Audiology ,Biology ,Deafness ,medicine.disease ,Article ,Mutation ,Genetics ,medicine ,OTOF ,otorhinolaryngologic diseases ,Missense mutation ,Humans ,Copy-number variation ,Hearing Loss, Central ,medicine.symptom ,Genetics (clinical) ,Genetic testing - Abstract
OBJECTIVE: To refine the natural history and genotype-phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD) through the analysis of audiograms and distortion product otoacoustic emissions (DPOAEs) in a diverse cohort of individuals with hearing loss. METHODS: Audiograms and DPOAEs were collected from individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and from the published literature. Comparative analysis was undertaken to determine genotype-phenotype relationships using a Monte Carlo algorithm. RESULTS: 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency pure tone average hearing loss thresholds with missense/missense and LoF/missense genotypes (average: 70.9, 76.0, and 73.4 dB hearing loss) compared with LoF/LoF genotypes (average: 88.5, 95.6, and 94.7 dB hearing loss) via Tukey’s test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347 respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of measured frequencies via DPOAE were lost per year in individuals with serial tests. CONCLUSIONS: Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. OTOF-related ANSD causes a unique pattern of variably progressive autosomal recessive auditory neuropathy that may be amenable to gene therapy in selected clinical scenarios.
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- 2021
12. 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
13. 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
14. Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder
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Nicole Fleischer, Grace M. Anbouba, Vandana Shashi, Thomas Meitinger, Damara Ortiz, Sumedha Ghate, Caleb Bupp, Maria J. Guillen Sacoto, Tiana M. Scott, Juliane Winkelmann, Felix Distelmaier, Sarah R Green, Dirk Klee, Carolyn R Serbinski, Lea Velsher, Michael T. Zimmermann, Meriel McEntagart, Gretchen Parsons, Patrick Yap, Evan H. Baugh, David S. Wargowski, Juan C Del Rey Jimenez, Anne K Olsen, Amy Armstrong-Javors, Victoria Mok Siu, Andrew Green, Nikita R. Dsouza, Elisabeth Graf, Sumit Punj, Matias Wagner, Anna Cereda, Naomi Meeks, Barbro Stadheim, Kirsty McWalter, Ingrid M. Wentzensen, Bert Callewaert, Rhonda E. Schnur, Emily Lancaster, Laurie A. Demmer, G. Bradley Schaefer, Kristin Lindstrom, Maria Iascone, Gonzalo Alonso Ramos-Rivera, Loren D M Pena, Amber Begtrup, Richard E. Person, Harrison Moore, Ameni Kdissa, Eric W. Klee, Dana Mittag, Jana Švantnerová, Ingrid Bader, Theresa Brunet, Johannes A. Mayr, Michael Zech, Jennifer A. Sullivan, Margot A. Cousin, Katharina Mayerhanser, Dagmar Wieczorek, Ralitza H. Gavrilova, and Daryl A. Scott
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Male ,Genotype ,ACETYLATION ,Autism Spectrum Disorder ,Chromosomal Proteins, Non-Histone ,autism ,Biology ,Pediatrics ,Whole Exome Sequencing ,Article ,Frameshift mutation ,Autism ,Developmental Delay ,Histone Acetylation ,Msl3 ,X-linked ,DOMAIN ,Genes, X-Linked ,MSL COMPLEX ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,medicine ,Medicine and Health Sciences ,Missense mutation ,Humans ,Exome ,Genetics (clinical) ,Exome sequencing ,MOF ,Genetics ,MSL3 ,MUTATIONS ,TRANSCRIPTIONAL REGULATION ,Macrocephaly ,histone acetylation ,Non-Histone ,medicine.disease ,ddc ,Chromosomal Proteins ,DNA-Binding Proteins ,developmental delay ,Phenotype ,Genes ,Autism spectrum disorder ,Female ,medicine.symptom ,DECAY ,DOSAGE COMPENSATION - Abstract
PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
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- 2021
15. 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
16. 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.
- Published
- 2020
17. 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
18. 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
19. Delineation of the First Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
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Eleanor G. Seaby, Marwan Shinawi, Raymond J. Louie, Aida Telegrafi, Suzanne M. Leal, Julien Buratti, Ana Petracovici, David B. Beck, Muhammad Arif Nadeem Saqib, Boris Keren, Sivagamy Sithambaram, Muhammad Zahid, Marie-Christine Nougues, Sander Pajusalu, Jill A. Fahrner, Eloise J. Prijoles, G. Bradley Schaefer, Dustin Baldridge, Trudie Cottrell, Regie Lyn P. Santos-Cortez, Roberto Bonasio, Tiia Reimand, Muhammad Ansar, Kirsty McWalter, Sofia Douzgou, Cyril Mignot, Siddharth Banka, Hannah W. Moore, Chongsheng He, Roger E. Stevenson, Katrin Õunap, and Renee Bend
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Genetics ,0303 health sciences ,biology ,Frameshift mutation ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Histone ,DNA demethylation ,DNA methylation ,biology.protein ,Mendelian inheritance ,symbols ,Epigenetics ,Global developmental delay ,Haploinsufficiency ,030217 neurology & neurosurgery ,030304 developmental biology - 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 of DNA (5mC) is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has been delineated. Here, we describe in detail the first Mendelian disorder caused by 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. Here we identify and characterize 11 cases of human TET3 deficiency in 8 families with the common phenotypic features of intellectual disability/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 with all but one occurring within the catalytic domain and most displaying hypomorphic function in a catalytic activity assay. TET3 deficiency shows substantial phenotypic overlap with other Mendelian disorders of the epigenetic machinery, including intellectual disability and growth abnormalities, underscoring shared disease mechanisms.
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- 2019
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20. 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
21. 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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Lynne M. Bird, Justin T. Jordan, Laura Dosa, Sébastien Perreault, Punita Gupta, Surya P. Rednam, Nicole J. Ullrich, Donald Basel, Linda M. Randolph, Leah W. Burke, Andrea Shugar, Angela Sharp, Ludwine Messiaen, Carey McDougall, Alicia Gomes, Andrea M. Lewis, Maurice J. Mahoney, Rachel K. Hachen, Marie T. McDonald, Katherine A. Rauen, Colette DeFilippo, Carmelo Piscopo, Maria Cristina Digilio, Sandra Janssens, Mary Ella M Pierpont, Lois J. Starr, Eric Legius, Michael F. Wangler, G. Bradley Schaefer, Arthur S. Aylsworth, Pamela Trapane, Ashraf Syed, Laurence E. Walsh, Alesha D. Hicks, Emily Wakefield, Robert Listernick, Nancy J. Mendelsohn, Elaine H. Zackai, Fortunato Lonardo, Dinel A. Pond, Robert S. Greenwood, Alessandro De Luca, Elizabeth K. Schorry, Rianne Oostenbrink, Katharina Wimmer, Ellen Denayer, Felicity Collins, Peter Kannu, Daryl A. Scott, S. Lane Rutledge, Yolanda Martin, Shelley K. Dills, Amedeo A. Azizi, Kristi J. Jones, David T. Miller, Gary Bellus, Yunjia Chen, Tom Callens, Magdalena Koczkowska, Kathleen Claes, Rick van Minkelen, Mayra Martinez Ojeda, Ashley Cannon, Bruce R. Korf, Cristin Griffis, Maria Blazo, Mari Mori, Veronica Saletti, Elizabeth Siqveland, Concepción Hernández-Chico, Pediatrics, and Clinical Genetics
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0301 basic medicine ,Male ,CHILDREN ,030105 genetics & heredity ,GUIDELINES ,neurofibroma ,Correlation ,Medicine and Health Sciences ,Type 1 Neurofibromatosis ,Neurofibroma ,Child ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,learning difficulties ,Genetics (clinical) ,Sequence Deletion ,Genetics ,Pediatric ,Genetics & Heredity ,Neurofibromin 1 ,Learning Disabilities ,ASSOCIATION ,genotype–phenotype correlation ,Plexiform ,Child, Preschool ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,NERVE SHEATH TUMORS ,Female ,p.Met992del ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Heterozygote ,VONRECKLINGHAUSEN NEUROFIBROMATOSIS ,Neurofibromatosis 1 ,Adolescent ,Clinical Sciences ,Mutation, Missense ,Biology ,genotype-phenotype correlation ,Article ,Genotype phenotype ,Neurofibromatosis ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Clinical Research ,medicine ,Humans ,Genetic Predisposition to Disease ,Clinical phenotype ,Preschool ,Gene ,neoplasms ,Genetic Association Studies ,Neurofibroma, Plexiform ,MUTATIONS ,OPTIC PATHWAY TUMORS ,Neurosciences ,Correction ,Biology and Life Sciences ,Infant ,SOUTH EAST WALES ,medicine.disease ,NOONAN SYNDROME ,nervous system diseases ,Brain Disorders ,030104 developmental biology ,NF1 ,Mutation ,Noonan syndrome ,TYPE-1 NEUROFIBROMATOSIS ,Missense - Abstract
PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care. ispartof: GENETICS IN MEDICINE vol:21 issue:4 pages:867-876 ispartof: location:United States status: published
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- 2019
22. 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
23. 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
24. De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function
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Peter Bauer, Jonathan Baets, G. Bradley Schaefer, Wenting Guo, Tine Deconinck, Bo Sun, Katherine L. Helbig, Sha Tang, Pranoot Tanpaiboon, Erika Palmaer, Peter De Jonghe, Florian Harmuth, Ingeborg Krägeloh-Mann, Matthis Synofzik, Rebecca Schüle, Ruiwu Wang, S. R. Wayne Chen, Ludger Schöls, Stephan Züchner, and Janina Gburek-Augustat
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0301 basic medicine ,Ataxia ,genetics [Inositol 1,4,5-Trisphosphate Receptors] ,Mutation, Missense ,Inositol 1,4,5-Trisphosphate ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Loss of Function Mutation ,metabolism [Inositol 1,4,5-Trisphosphate] ,Genetics ,medicine ,Missense mutation ,Humans ,Inositol 1,4,5-Trisphosphate Receptors ,metabolism [Calcium] ,ddc:610 ,Child ,Gene ,Biology ,Genetics (clinical) ,Spinocerebellar Degenerations ,Mutation ,business.industry ,medicine.disease ,Phenotype ,metabolism [Inositol 1,4,5-Trisphosphate Receptors] ,genetics [Spinocerebellar Degenerations] ,ITPR1 protein, human ,3. Good health ,Chemistry ,030104 developmental biology ,HEK293 Cells ,pathology [Spinocerebellar Degenerations] ,Cohort ,Spinocerebellar ataxia ,Calcium ,Female ,Human medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca2+ release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca2+ release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.
- Published
- 2018
25. 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
26. 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
27. 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
28. 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
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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.
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- 2015
29. Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors
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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
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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.
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- 2015
30. Adults' perceptions of genetic counseling and genetic testing
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Gwendolyn M. Reiser, Brigette Soltis-Vaughan, Jan R. Atwood, G. Bradley Schaefer, and Julia F. Houfek
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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.
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- 2015
31. Aplastic Anemia in Two Patients with Sex Chromosome Aneuploidies
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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
32. Whole exome sequencing reveals EP300 mutation in mildly affected female: expansion of the spectrum
- Author
-
Bonnie Sullivan, Elizabeth A. Sellars, and G. Bradley Schaefer
- Subjects
0301 basic medicine ,Genetics ,EP300 ,Rubinstein–Taybi syndrome ,business.industry ,Case Report ,General Medicine ,Case Reports ,030105 genetics & heredity ,medicine.disease ,CREBBP ,Phenotype ,whole exome sequencing ,03 medical and health sciences ,Mutation (genetic algorithm) ,medicine ,business ,Exome ,Exome sequencing - Abstract
Key Clinical Message Rubinstein–Taybi syndrome is associated with intellectual and physical features. CREBBP and EP300 are causative. Few cases of EP300 mutations are reported. We report a case with mild features of RSTS and EP300 mutation on exome sequencing. This illustrates the utility of exome sequencing to expand every genetic phenotype.
- Published
- 2016
33. A unique case series of autosomal recessive bestrophinopathy exhibiting multigenerational inheritance
- Author
-
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
34. Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome
- Author
-
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
35. Multi-Tiered Analysis of Brain Injury in Neonates With Congenital Heart Disease
- Author
-
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
36. Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features
- Author
-
Megan T. Cho, Lindsay B. Henderson, Paulien A Terhal, Wendy K. Chung, G. Bradley Schaefer, Virginie J. M. Verhoeven, Patricia G. Wheeler, Kristin G. Monaghan, Saleem Malik, Koen L.I. van Gassen, Noelle R. Danylchuk, Rick Person, Marjon van Slegtenhorst, Stephanie Burns Wechsler, Hallie Steinfeld, Kyle Retterer, and Clinical Genetics
- Subjects
0301 basic medicine ,Male ,Adolescent ,Developmental Disabilities ,Human immunodeficiency virus (HIV) ,Biology ,medicine.disease_cause ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Enhancer binding ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,medicine ,Genetics ,Journal Article ,Humans ,Genetics(clinical) ,Child ,Transcription factor ,Genetics (clinical) ,Exome sequencing ,Mutation ,Developmental Delay ,medicine.disease ,Body Dysmorphic Disorders ,Human genetics ,DNA-Binding Proteins ,030104 developmental biology ,Child, Preschool ,Whole-exome sequencing ,Body dysmorphic disorder ,Female ,De novo ,HIVEP2 ,Transcription Factors - Abstract
Human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay.
- Published
- 2016
37. Lessons from a pair of siblings with BPAN
- Author
-
Melanie A Jones, G. Bradley Schaefer, Francisca Millan, Yuri A. Zarate, Jane Juusola, Michael C. Kruer, Julie R. Jones, and Annette Vertino-Bell
- Subjects
0301 basic medicine ,Adult ,Male ,Heterozygote ,Adolescent ,Neurodegeneration with brain iron accumulation ,Short Report ,Neuroaxonal Dystrophies ,Germline mosaicism ,Biology ,Asymptomatic ,Germline ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,WDR45 ,Intellectual disability ,Genetics ,medicine ,Humans ,Exome ,Gene ,Genetics (clinical) ,Germ-Line Mutation ,Hemizygote ,Chromosomes, Human, X ,Mosaicism ,Neurodegeneration ,Genetic Diseases, X-Linked ,medicine.disease ,Iron Metabolism Disorders ,Pedigree ,030104 developmental biology ,Female ,medicine.symptom ,Corrigendum ,Carrier Proteins ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.
- Published
- 2016
38. In memory of Murray Feingold (1930-2015)
- Author
-
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
39. De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features
- Author
-
Kyle Retterer, Aida Telegrafi, Yong-hui Jiang, Akemi J. Tanaka, Omar A. Rahman, Wendy K. Chung, Julie Kaylor, Julie R. Jones, G. Bradley Schaefer, Allyn McConkie-Rosell, Catherine Nowak, Bethany Friedman, Megan T. Cho, Ganka Douglas, Kristin G. Monaghan, and Jessica Douglas
- Subjects
Genetics ,Zinc finger ,Research Report ,Microcephaly ,Cell division ,Chromosome ,General Medicine ,medicine.disease ,Intellectual disability ,medicine ,Global developmental delay ,congenital microcephaly ,Psychology ,intellectual disability, severe ,Metaphase ,Mitosis ,severe global developmental delay - Abstract
We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore–microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.
- Published
- 2016
40. 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
41. Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes
- Author
-
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
42. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations
- Author
-
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
43. 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
44. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders
- Author
-
G. Bradley Schaefer and Nancy J. Mendelsohn
- Subjects
Medical home ,medicine.medical_specialty ,Modalities ,business.industry ,Genetics, Medical ,ACMG Practice Guidelines ,Socialization ,MEDLINE ,Genetic Counseling ,pervasive developmental disorders ,Geneticist ,medicine.disease ,diagnostic yield ,Asperger syndrome ,Etiology ,medicine ,Humans ,Autism ,Medical genetics ,Genetic Testing ,tiered evaluations ,Autistic Disorder ,Psychiatry ,business ,Genetics (clinical) - Abstract
The autism spectrum disorders are a collection of conditions, which have, in common, impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased markedly over the past decade. In addition, a large amount of attention has been paid to these conditions among lay and professional groups. These influences have resulted in a marked increase in the number of referrals to clinical geneticists for evaluation of persons with autism spectrum disorders. The primary role of the geneticist in this process is to define etiology, if possible, and to provide counseling and contribute to case management based on the results of such investigations. In deciding upon the appropriate evaluation scheme for a particular patient, the geneticist must consider a host of different factors. Such considerations would include (1) Assuring an accurate diagnosis of autism before proceeding with any investigation. (2) Discussing testing options, diagnostic yields, and patient investment before proceeding with an evaluation. (3) Communication and coordination with the patient's medical home. (4) Assessing the continuously expanding and evolving list of available laboratory testing modalities in light of evidence-based medicine. (5) Recognizing expanded phenotypes of well-described syndromic and metabolic conditions that encompass autism spectrum disorders. (6) Defining an individualized evaluation scheme based on the unique history and clinical features of a given patient. The guidelines in this article have been developed to assist the clinician in the consideration of these factors.
- Published
- 2008
45. 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
46. Phenotypic Modifications of Patients with Full Chromosome Aneuploidies and Concurrent Suspected or Confirmed Second Diagnoses
- Author
-
G. Bradley Schaefer, Lois J. Starr, Katherine A. Bosanko, Rebecca D. Ganetzky, Elaine H. Zackai, Yuri A. Zarate, and Elizabeth J. Bhoj
- Subjects
Marfan syndrome ,Male ,Down syndrome ,Pediatrics ,medicine.medical_specialty ,Aneuploidy ,Chromosome Disorders ,Comorbidity ,Biology ,Article ,Congenital Abnormalities ,Craniofacial microsomia ,Turner syndrome ,Genetics ,medicine ,Humans ,Medical diagnosis ,Child ,Genetics (clinical) ,Chromosome Aberrations ,Genetic Diseases, Inborn ,Infant, Newborn ,Chromosome ,Infant ,medicine.disease ,Phenotype ,Child, Preschool ,Female - Abstract
The coexistence of two or more distinct genetic conditions is known to be a rare phenomenon. Full chromosome aneuploidies can be associated with a broad variety of cytogenetic abnormalities or single gene disorders resulting in phenotypic modifications that confuse the diagnostic process. We present six patients with primary aneuploidies and a suspected or confirmed secondary genetic diagnosis or unusual birth defect. Among the cases included, we report the first patients with concurrent Down syndrome in combination with Prader-Willi, Craniofacial Microsomia, and Stickler syndromes. We also describe only the second reported case of a neonate with Down syndrome and Marfan syndrome. In all cases, the unusual clinical presentations lead to further molecular cytogenetic studies as well as single or multi-gene molecular evaluations. We make emphasis on the importance of entertaining the possibility of coexistent diagnoses when the phenotype is not what is expected for aneuploidies rather than attributing the unusual findings to rare or unreported associations of the primary aneuploidy.
- Published
- 2015
47. 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
48. A Tribute to Henry H. Turner, MD (1892???1970)
- Author
-
G Bradley Schaefer and Harris D. Riley
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,Art history ,Medicine ,Tribute ,business - Published
- 2004
49. Medical Genetics
- Author
-
G. Bradley Schaefer, James N. Thompson, G. Bradley Schaefer, and James N. Thompson
- Abstract
A complete introductory text on how to integrate basic genetic principles into the practice of clinical medicine Medical Genetics is the first text to focus on the everyday application of genetic assessment and its diagnostic, therapeutic, and preventive implications in clinical practice. It is intended to be a text that you can use throughout medical school and refer back to when questions arise during residency and, eventually, practice. Medical Genetics is written as a narrative where each chapter builds upon the foundation laid by previous ones. Chapters can also be used as stand-alone learning aids for specific topics. Taken as a whole, this timely book delivers a complete overview of genetics in medicine. You will find in-depth, expert coverage of such key topics as: The structure and function of genes Cytogenetics Mendelian inheritance Mutations Genetic testing and screening Genetic therapies Disorders of organelles Key genetic diseases, disorders, and syndromes Each chapter of Medical Genetics is logically organized into three sections: Background and Systems – Includes the basic genetic principles needed to understand the medical application Medical Genetics – Contains all the pertinent information necessary to build a strong knowledge base for being successful on every step of the USMLE Case Study Application – Incorporates case study examples to illustrate how basic principles apply to real-world patent care Today, with every component of health care delivery requiring a working knowledge of core genetic principles, Medical Genetics is a true must-read for every clinician.
- Published
- 2013
50. Windows Into the Mind
- Author
-
G. Bradley Schaefer and Kathy Coufal
- Subjects
World Wide Web ,Speech and Hearing ,Computer science - Published
- 2003
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