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Comprehensive genomic analysis of patients with disorders of cerebral cortical development

2018; Springer Nature; Volume: 26; Issue: 8 Linguagem: Inglês

10.1038/s41431-018-0137-z

1476-5438

Wojciech Wiszniewski, Paweł Gawliński, Tomasz Gambin, Monika Bekiesińska‐Figatowska, Ewa Obersztyn, Dorota Antczak‐Marach, Zeynep H. Coban Akdemir, Tamar Harel, Ender Karaca, Marta Jurek, Katarzyna Sobecka, Beata Nowakowska, Małgorzata Kruk, Iwona Terczyńska, Alicja Goszczańska‐Ciuchta, Mariola Rudzka‐Dybała, Ewa Jamroz, Antoni Pyrkosz, Anna Jakubiuk‐Tomaszuk, Piotr Iwanowski, Dorota Gieruszczak‐Białek, Małgorzata Piotrowicz, Maria Sąsiadek, Iwona Kochanowska, Barbara Gurda, Barbara Steinborn, Mateusz Dawidziuk, Jennifer Castañeda, Paweł Własienko, Natalia Bezniakow, Shalini N. Jhangiani, Dorota Hoffman‐Zacharska, Jerzy Bal, Elżbieta Szczepanik, Eric Boerwinkle, Richard A. Gibbs, James R. Lupski,

Genetics and Neurodevelopmental Disorders

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.