Browsing by Author "Bayrak-Toydemir, Pinar"

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    Characterization of Reference Materials for Spinal Muscular Atrophy Genetic Testing: A Genetic Testing Reference Materials Coordination Program Collaborative Project
    (Elsevier, 2021) Prior, Thomas W.; Bayrak-Toydemir, Pinar; Lynnes, Ty C.; Mao, Rong; Metcalf, James D.; Muralidharan, Kasinathan; Iwata-Otsubo, Aiko; Pham, Ha T.; Pratt, Victoria M.; Qureshi, Shumaila; Requesens, Deborah; Shen, Junqing; Vetrini, Francesco; Kalman, Lisa; Medicine, School of Medicine
    Spinal muscular atrophy (SMA) is an autosomal recessive disorder predominately caused by bi-allelic loss of the SMN1 gene. Increased copies of SMN2, a low functioning nearly identical paralog, are associated with a less severe phenotype. SMA was recently recommended for inclusion in newborn screening. Clinical laboratories must accurately measure SMN1 and SMN2 copy number to identify SMA patients and carriers, and to identify individuals likely to benefit from therapeutic interventions. Having publicly available and appropriately characterized reference materials with various combinations of SMN1 and SMN2 copy number variants is critical to assure accurate SMA clinical testing. To address this need, the CDC-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and the Coriell Institute for Medical Research, has characterized 15 SMA reference materials derived from publicly available cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using three different methods. The characterized samples had zero to four copies of SMN1 and zero to five copies SMN2. The samples also contained clinically important allele combinations (eg, zero copies SMN1, three copies SMN2), and several had markers indicative of an SMA carrier. These and other reference materials characterized by the Genetic Testing Reference Materials Coordination Program are available from the Coriell Institute and are proposed to support the quality of clinical laboratory testing.
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    De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations
    (Elsevier, 2022-09) Dias, Kerith-Rae; Carlston, Colleen M.; Blok, Laura E. R.; De Hayr , Lachlan; Nawaz, Urwah; Evans, Carey-Anne; Bayrak-Toydemir, Pinar; Htun, Stephanie; Zhu, Ying; Ma, Alan; Lynch, Sally Ann; Moorwood, Catherine; Stals , Karen; Ellard, Sian; Bainbridge, Matthew N.; Friedman, Jennifer; Pappas, John G.; Rabin , Rachel; Nowak, Catherine B.; Douglas, Jessica; Wilson, Theodore E.; Guillen Sacoto, Maria J.; Mullegama, Sureni V.; Palculict , Timothy Blake; Kirk, Edwin P.; Pinner, Jason R.; Edwards, Matthew; Montanari, Francesca; Graziano, Claudio; Pippucci, Tommaso; Dingmann, Bri; Glass , Ian; Mefford , Heather C.; Shimoji , Takeyoshi; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Streff, Haley; Schaaf, Christian P.; Slavotinek, Anne M.; Voineagu , Irina; Carey, John C.; Buckley, Michael F.; Schenck, Annette; Harvey, Robert J.; Roscioli , Tony; Medical and Molecular Genetics, School of Medicine
    Purpose ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.