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Eur J Hum Genet. 2018 Aug;26(8):1121-1131. doi: 10.1038/s41431-018-0137-z. Epub 2018 Apr 30.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. wiszniew@ohsu.edu.
2
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. wiszniew@ohsu.edu.
3
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA. wiszniew@ohsu.edu.
4
Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
5
Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
6
Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland.
7
Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
9
School of Medicine in Katowice, Department of Pediatrics and Developmental Age Neurology, Medical University of Silesia, Katowice, Poland.
10
Department of Medical Genetics, University of Rzeszow, Rzeszow, Poland.
11
Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok, Bialystok, Poland.
12
Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
13
Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland.
14
Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.
15
Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
16
Individual Medical Practice in Pediatric Neurology, Szczecin, Poland.
17
Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland.
18
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
19
Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX, USA.
20
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
21
Texas Children's Hospital, Houston, TX, USA.

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 genesĀ  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.

PMID:
29706646
PMCID:
PMC6057976
[Available on 2019-08-01]
DOI:
10.1038/s41431-018-0137-z
[Indexed for MEDLINE]

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