TY - JOUR

T1 - High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations

AU - Kariminejad, Roxana

AU - Lind-Thomsen, Allan

AU - Tümer, Zeynep

AU - Erdogan, Fikret

AU - Ropers, Hans H

AU - Tommerup, Niels

AU - Ullmann, Reinhard

AU - Møller, Rikke S

N1 - © 2011 Wiley Periodicals, Inc.

PY - 2011/12

Y1 - 2011/12

N2 - During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein-protein network analysis. Based on these analyses, we propose that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors.

AB - During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein-protein network analysis. Based on these analyses, we propose that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors.

KW - Agenesis of Corpus Callosum

KW - Brain

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Comparative Genomic Hybridization

KW - DNA Copy Number Variations

KW - Epilepsy

KW - Female

KW - Gene Dosage

KW - Gene Frequency

KW - Humans

KW - Intellectual Disability

KW - Magnetic Resonance Imaging

KW - Male

KW - Nervous System Malformations

KW - Phenotype

KW - Proteins

KW - Tomography Scanners, X-Ray Computed

U2 - 10.1002/humu.21585

DO - 10.1002/humu.21585

M3 - Journal article

C2 - 21882292

VL - 32

SP - 1427

EP - 1435

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 12

ER -