TY - JOUR
T1 - Comprehensive genomic analysis of patients with disorders of cerebral cortical development
AU - Wiszniewski, Wojciech
AU - Gawlinski, Pawel
AU - Gambin, Tomasz
AU - Bekiesinska-Figatowska, Monika
AU - Obersztyn, Ewa
AU - Antczak-Marach, Dorota
AU - Akdemir, Zeynep Hande Coban
AU - Harel, Tamar
AU - Karaca, Ender
AU - Jurek, Marta
AU - Sobecka, Katarzyna
AU - Nowakowska, Beata
AU - Kruk, Malgorzata
AU - Terczynska, Iwona
AU - Goszczanska-Ciuchta, Alicja
AU - Rudzka-Dybala, Mariola
AU - Jamroz, Ewa
AU - Pyrkosz, Antoni
AU - Jakubiuk-Tomaszuk, Anna
AU - Iwanowski, Piotr
AU - Gieruszczak-Bialek, Dorota
AU - Piotrowicz, Malgorzata
AU - Sasiadek, Maria
AU - Kochanowska, Iwona
AU - Gurda, Barbara
AU - Steinborn, Barbara
AU - Dawidziuk, Mateusz
AU - Castaneda, Jennifer
AU - Wlasienko, Pawel
AU - Bezniakow, Natalia
AU - Jhangiani, Shalini N.
AU - Hoffman-Zacharska, Dorota
AU - Bal, Jerzy
AU - Szczepanik, Elzbieta
AU - Boerwinkle, Eric
AU - Gibbs, Richard A.
AU - Lupski, James R.
N1 - Publisher Copyright:
© 2018, European Society of Human Genetics.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41431-018-0137-z
DO - 10.1038/s41431-018-0137-z
M3 - Article
C2 - 29706646
AN - SCOPUS:85046077463
SN - 1018-4813
VL - 26
SP - 1121
EP - 1131
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 8
ER -