1. Comprehensive genomic analysis of patients with disorders of cerebral cortical development
- Author
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Iwona Kochanowska, Eric Boerwinkle, Barbara Steinborn, Beata Nowakowska, James R. Lupski, Tomasz Gambin, Antoni Pyrkosz, Mateusz Dawidziuk, Marta Jurek, Dorota Hoffman-Zacharska, Alicja Goszczańska-Ciuchta, Wojciech Wiszniewski, Ewa Jamroz, Jerzy Bal, Ender Karaca, Barbara Gurda, Tamar Harel, Piotr S. Iwanowski, Małgorzata Piotrowicz, Dorota Antczak-Marach, Natalia Bezniakow, Anna Jakubiuk-Tomaszuk, Dorota Gieruszczak-Białek, Iwona Terczyńska, Shalini N. Jhangiani, Elżbieta Szczepanik, Maria M. Sasiadek, Ewa Obersztyn, Pawel Wlasienko, Zeynep Coban Akdemir, Monika Bekiesińska-Figatowska, Małgorzata Kruk, Jennifer Castaneda, Mariola Rudzka-Dybała, Pawel Gawlinski, Katarzyna Sobecka, and Richard A. Gibbs
- Subjects
0301 basic medicine ,Male ,Candidate gene ,Microarray ,DNA Copy Number Variations ,Nerve Tissue Proteins ,Receptors, Cell Surface ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Epilepsy ,Genetic Heterogeneity ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Exome ,Copy-number variation ,Genetics (clinical) ,Genetic heterogeneity ,medicine.disease ,Cadherins ,Phenotype ,Genetic architecture ,Malformations of Cortical Development ,030104 developmental biology ,Female ,030217 neurology & neurosurgery - 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.
- Published
- 2017