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Comprehensive genomic analysis of patients with disorders of cerebral cortical development.
Wiszniewski, Wojciech; Gawlinski, Pawel; Gambin, Tomasz; Bekiesinska-Figatowska, Monika; Obersztyn, Ewa; Antczak-Marach, Dorota; Akdemir, Zeynep Hande Coban; Harel, Tamar; Karaca, Ender; Jurek, Marta; Sobecka, Katarzyna; Nowakowska, Beata; Kruk, Malgorzata; Terczynska, Iwona; Goszczanska-Ciuchta, Alicja; Rudzka-Dybala, Mariola; Jamroz, Ewa; Pyrkosz, Antoni; Jakubiuk-Tomaszuk, Anna; Iwanowski, Piotr; Gieruszczak-Bialek, Dorota; Piotrowicz, Malgorzata; Sasiadek, Maria; Kochanowska, Iwona; Gurda, Barbara; Steinborn, Barbara; Dawidziuk, Mateusz; Castaneda, Jennifer; Wlasienko, Pawel; Bezniakow, Natalia; Jhangiani, Shalini N; Hoffman-Zacharska, Dorota; Bal, Jerzy; Szczepanik, Elzbieta; Boerwinkle, Eric; Gibbs, Richard A; Lupski, James R.
Afiliação
  • Wiszniewski W; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. wiszniew@ohsu.edu.
  • Gawlinski P; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. wiszniew@ohsu.edu.
  • Gambin T; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA. wiszniew@ohsu.edu.
  • Bekiesinska-Figatowska M; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Obersztyn E; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Antczak-Marach D; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
  • Akdemir ZHC; Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland.
  • Harel T; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Karaca E; Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
  • Jurek M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Sobecka K; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Nowakowska B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Kruk M; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Terczynska I; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Goszczanska-Ciuchta A; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Rudzka-Dybala M; Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
  • Jamroz E; Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
  • Pyrkosz A; Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
  • Jakubiuk-Tomaszuk A; Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
  • Iwanowski P; School of Medicine in Katowice, Department of Pediatrics and Developmental Age Neurology, Medical University of Silesia, Katowice, Poland.
  • Gieruszczak-Bialek D; Department of Medical Genetics, University of Rzeszow, Rzeszow, Poland.
  • Piotrowicz M; Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok, Bialystok, Poland.
  • Sasiadek M; Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
  • Kochanowska I; Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
  • Gurda B; Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland.
  • Steinborn B; Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.
  • Dawidziuk M; Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
  • Castaneda J; Individual Medical Practice in Pediatric Neurology, Szczecin, Poland.
  • Wlasienko P; Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland.
  • Bezniakow N; Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland.
  • Jhangiani SN; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Hoffman-Zacharska D; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Bal J; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Szczepanik E; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Boerwinkle E; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
  • Gibbs RA; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Lupski JR; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
Eur J Hum Genet ; 26(8): 1121-1131, 2018 08.
Article em En | MEDLINE | ID: mdl-29706646
ABSTRACT
Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Polimorfismo de Nucleotídeo Único / Malformações do Desenvolvimento Cortical / Variações do Número de Cópias de DNA / Exoma Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male Idioma: En Revista: Eur J Hum Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Polimorfismo de Nucleotídeo Único / Malformações do Desenvolvimento Cortical / Variações do Número de Cópias de DNA / Exoma Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male Idioma: En Revista: Eur J Hum Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos