These authors contributed equally to the work.
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci
Article first published online: 21 FEB 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 84, Issue 6, pages 560–565, December 2013
How to Cite
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci., , , , , , , .
The authors declare no conflict of interests.
- Issue published online: 28 OCT 2013
- Article first published online: 21 FEB 2013
- Accepted manuscript online: 25 JAN 2013 09:35AM EST
- Manuscript Revised: 17 JAN 2013
- Manuscript Accepted: 17 JAN 2013
- Manuscript Received: 7 SEP 2012
- Deutsche Forschungsgemeinschaft. Grant Numbers: KU 1240/6-1, RO 3660/1-1
- chromosomal rearrangement;
- intellectual disability;
- modifier gene;
Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1–3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding α7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy.