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

Abstract

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.

Brain malformations and mutations in α‐ and β‐tubulin genes: a review of the literature and description of two new cases

“…1 MCDs may be a result of environmental causes such as congenital infections (particularly the toxoplasmosis, other infections, rubella, cytomegalovirus, herpes simplex virus [TORCH] complex), 2 localized or diffuse in utero ischaemia, 3 or genetic causes such as chromosomal rearrangements and single-gene disorders. 4 These latter are considered relevant causes of MCDs. The latest classification of MCDs is based on both magnetic resonance imaging (MRI) findings and mutations in genes involved in cortical development.…”

Epileptogenic malformations of cortical development: when evolution goes awry

“…WES, in particular, has led to the identification of more than 150 novel disease genes with numerous ones implicated in brain development (16). At least one rare copy-number variation was detected in 22.5% of patients from a cohort of 169 patients with various structural brain malformations investigated by array comparative genomic hybridization (3). Due to all these achievements, more and more MCD patients and their families are able to profit from the advantages given by exact genetic diagnosis, including natural history and recurrence risks prognostication, patient management decisions, options for prenatal testing and relief of psychological burden, all of them having a significant positive impact on a patient and a family.…”

“…The biological pathways include cell-cycle regulation in many steps (including mitosis and cell division), apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration and many inborn errors of metabolism (2). However, the genetic cause still remains unidentified in the majority of cases (3).…”

Following the genes: a framework for animal modeling of psychiatric disorders

“…Copy number variants (deletions or duplication of chromosomal segments, often affecting multiple genes) have been most readily identified and make up an important class of causal mutations in schizophrenia [42,45-51], autism [41,52-54], attention deficit-hyperactivity disorder [55-58], Tourette syndrome [59], developmental delay and mental retardation [60,61], epilepsy [62] and cortical malformations [63]. Whole-exome and whole-genome sequencing approaches are now also identifying large numbers of point mutations individually responsible for psychiatric conditions [64-71].…”