Copy number variants highlight candidate genes for neurological conditions

Copy number variants highlight candidate genes for neurological conditions
2 June 2010 | By Dr Gurdeep Sagoo | Research article

In the UK, around 1 in every 131 people has epilepsy (according to the Joint Epilepsy Council). Epilepsy is a common neurological condition which causes recurrent seizures due to the over-activity of the brain. There are over 50 distinct epilepsy syndromes and although various causes of epilepsy are known, such as brain damage or brain tumours, idiopathic epilepsy occurs in the absence of an identifiable cause, with genetic factors thought to contribute (see previous news). A new study published in the journal PLoS Genetics has identified copy number variants (CNVs) in regions of interest not only in epilepsy but also other neurological conditions such as intellectual disability, autism, and schizophrenia.

The study by Mefford et al. reports a whole-genome oligonucleotide array comparative genomic hybridisation of 517 individuals of European descent with various idiopathic epilepsies [Mefford et al. PLoS Genet 6(5): e1000962. doi:10.1371/journal.pgen.1000962]. Patients were collected from five centres and included diagnoses such as idiopathic generalised epilepsy or IGE, idiopathic focal epilepsy, and other forms of epilepsy. In 46 individuals, one or more rare CNVs ranging in size from 13kb to 15.9Mb were identified. These variants were not identified in a previously reported cohort of nearly 2,500 controls, suggesting that they may be causal.


The identified CNVs also involved genes or regions that have been previously implicated in other neurological phenotypes such as autism. Deletions on chromosomes 15 (15q11.2 and 15q13.3) and 16 (16p13.1) were mostly observed in IGE individuals. On chromosome 15q11.2, the candidate gene is CHRNA7, a subunit of the nicotinic acetylcholine receptor, although the epidemiological evidence from the small studies conducted to date is mixed. Chromosome 16p13.1 is a novel susceptibility locus for epilepsy. Several other candidate genes were also reported including CNTNAP2, CNTNAP4, and AUT2. The authors suggest that these regions and genes should be investigated as candidate genes with possible roles both across subtypes of IGE as well as in specific subtypes. Overlapping regions with other neurological conditions suggests some common aetiological genetic factors across these conditions.

Comment: The use of microarrays for genetic analysis is becoming more commonly applied (see previous news) including databases cataloguing variation observed with clinical or healthy phenotypes to aid with clinical evaluation of identified CNVs (see previous news). This paper is the first whole-genome array-CGH analysis in epilepsy and has identified some previously known regions and candidate genes (see previous news) as well as some novel regions that warrant follow-up work. This work is based on the common disease, rare variant model of disease where common diseases are caused by multiple rare variants. Finding these rare variants requires large sample sizes and high resolution technology such as array-CGH and some difficulty still remains in determining whether a CNV is causal or benign.

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