Comprehensive genomic analysis of patients with disorders of cerebral cortical development
Wojciech Wiszniewski , Paweł Gawliński , Tomasz Gambin , Monika Bekiesinska-Figatowska , Ewa Obersztyn , Dorota Antczak-Marach , Zeynep Hande Coban Akdemir , Tamar Harel , Ender Karaca , M. Jurek , Katarzyna Sobecka , Beata Nowakowska , Małgorzata Kruk , Iwona Terczynska , Alicja Goszczanska-Ciuchta , Mariola Rudzka-Dybala , Ewa Jamroz , Antoni Pyrkosz , Anna Jakubiuk-Tomaszuk , Piotr Iwanowski , Dorota Gieruszczak-Bialek , Malgorzata Piotrowicz , Maria Sasiadek , Iwona Kochanowska , Barbara Gurda , Barbara Steinborn , Mateusz Dawidziuk , Jennifer Castaneda , Pawel Wlasienko , Natalia Bezniakow , Shalini N. Jhangiani , Dorota Hoffman-Zacharska , Jerzy Bal , Elzbieta Szczepanik , Eric Boerwinkle , Richard A. Gibbs , James R. Lupski
AbstractMalformations 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.
|Journal series||European Journal of Human Genetics, ISSN 1018-4813, (A 35 pkt)|
|Publication size in sheets||0.5|
|Score|| = 35.0, 04-09-2018, ArticleFromJournal|
= 35.0, 04-09-2018, ArticleFromJournal
|Publication indicators||: 2016 = 4.287 (2) - 2016=3.977 (5)|
|Citation count*||1 (2018-11-13)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.