Abstract
Rare copy number variants (CNVs) are frequently associated with common neurological disorders such as mental retardation (MR; learning disability), autism, and schizophrenia. CNV screening in clinical practice is limited because pathological CNVs cannot be distinguished routinely from benign CNVs, and because genes underlying patients' phenotypes remain largely unknown. Here, we present a novel, statistically robust approach that forges links between 148 MR–associated CNVs and phenotypes from ∼5,000 mouse gene knockout experiments. These CNVs were found to be significantly enriched in two classes of genes, those whose mouse orthologues, when disrupted, result in either abnormal axon or dopaminergic neuron morphologies. Additional enrichments highlighted correspondences between relevant mouse phenotypes and secondary presentations such as brain abnormality, cleft palate, and seizures. The strength of these phenotype enrichments (>100% increases) greatly exceeded molecular annotations (<30% increases) and allowed the identification of 78 genes that may contribute to MR and associated phenotypes. This study is the first to demonstrate how the power of mouse knockout data can be systematically exploited to better understand genetically heterogeneous neurological disorders.
Highlights
Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, and is associated with functional deficits in adaptive behaviour, such as daily-living skills, social skills and communication
We found that MR–associated copy number variations (CNVs) contain greater than expected numbers of genes that give specific nervous system phenotypes when disrupted in the mouse
Does this study confirm that CNVs frequently cause MR, but it narrows down the list of genes whose changes lead to this disorder from thousands to several dozen
Summary
Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, and is associated with functional deficits in adaptive behaviour, such as daily-living skills, social skills and communication. This disorder affects 1%–3% of the population and results from extraordinarily heterogeneous environmental and genetic causes [1]. Visible chromosomal rearrangements detected by routine chromosome analysis are the cause for MR in ,5%–10% of patients [3] Such rearrangements represent gains or losses of more than 5–10 Mb of DNA and affect many genes thereby almost inevitably leading to developmental abnormalities during embryogenesis. The most common effect of these variants is cognitive impairment, but they can be frequently associated with other abnormalities such as heart defects, seizures and dysmorphic features [4]
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