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


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.
Author Wojciech Wiszniewski
Wojciech Wiszniewski,,
, Paweł Gawliński - Institute of Mother and Child, Department of Diagnostic Imaging (IMD/ZDO)
Paweł Gawliński,,
, Tomasz Gambin (FEIT / IN)
Tomasz Gambin,,
- The Institute of Computer Science
, Monika Bekiesinska-Figatowska - Institute of Mother and Child, Department of Diagnostic Imaging (IMD/ZDO)
Monika Bekiesinska-Figatowska,,
, Ewa Obersztyn
Ewa Obersztyn,,
, Dorota Antczak-Marach
Dorota Antczak-Marach,,
, Zeynep Hande Coban Akdemir
Zeynep Hande Coban Akdemir,,
, Tamar Harel
Tamar Harel,,
, Ender Karaca
Ender Karaca,,
, M. Jurek
M. Jurek,,
et al.`
Journal seriesEuropean Journal of Human Genetics, ISSN 1018-4813, (A 35 pkt)
Issue year2018
Publication size in sheets0.5
ASJC Classification2716 Genetics(clinical); 1311 Genetics
projectDevelopment of new algorithms in the areas of software and computer architecture, artificial intelligence and information systems and computer graphics . Project leader: Arabas Jarosław, , Phone: +48 22 234 7432, start date 01-06-2017, end date 31-10-2018, II/2017/DS/1, Completed
WEiTI Działalność statutowa
Languageen angielski
Score (nominal)35
ScoreMinisterial score = 35.0, ArticleFromJournal
Ministerial score (2013-2016) = 35.0, ArticleFromJournal
Publication indicators WoS Citations = 1; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.264; WoS Impact Factor: 2017 = 3.636 (2) - 2017=3.694 (5)
Citation count*2 (2019-04-20)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.