Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

TitleComprehensive genomic analysis of patients with disorders of cerebral cortical development.
Publication TypeJournal Article
Year of Publication2018
AuthorsWiszniewski, W, Gawlinski, P, Gambin, T, Bekiesinska-Figatowska, M, Obersztyn, E, Antczak-Marach, D, Akdemir, ZHande Coba, Harel, T, Karaca, E, Jurek, M, Sobecka, K, Nowakowska, B, Kruk, M, Terczynska, I, Goszczanska-Ciuchta, A, Rudzka-Dybala, M, Jamroz, E, Pyrkosz, A, Jakubiuk-Tomaszuk, A, Iwanowski, P, Gieruszczak-Bialek, D, Piotrowicz, M, Sasiadek, M, Kochanowska, I, Gurda, B, Steinborn, B, Dawidziuk, M, Castaneda, J, Wlasienko, P, Bezniakow, N, Jhangiani, SN, Hoffman-Zacharska, D, Bal, J, Szczepanik, E, Boerwinkle, E, Gibbs, RA, Lupski, JR
JournalEur J Hum Genet
Date Published2018 Aug
KeywordsCadherins, DNA Copy Number Variations, Exome, Female, Genetic Heterogeneity, Humans, Male, Malformations of Cortical Development, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Cell Surface

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.

Alternate JournalEur J Hum Genet
PubMed ID29706646
PubMed Central IDPMC6057976
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States

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