Study approval: Ethical approval was obtained from the local Ethics Committees. All participants gave written informed consent.
Sequence analysis of 17 NRXN1 deletions
Article first published online: 25 SEP 2013
© 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 165, Issue 1, pages 52–61, January 2014
How to Cite
2013. Sequence Analysis of 17 NRXN1 Deletions. 165B:52–61., , , , , , , , , , .
Competing interests: All authors included on the paper have declared no conflict of interest. Dr. Werge has served as a lecturer for and consultant to H. Lundbeck A/S.
- Issue published online: 13 DEC 2013
- Article first published online: 25 SEP 2013
- Manuscript Accepted: 27 AUG 2013
- Manuscript Received: 18 MAR 2013
- Lundbeck Foundation. Grant Number: R34-A3243
- Danish National Advanced Technology Foundation. Grant Number: 001-2009-2
- Danish Council for Independent Research in Medical Sciences
- Danish Psychiatric Research Foundation
- European Union. Grant Number: LSHM-CT-2006-037761
Vol. 165, Issue 3, 261, Article first published online: 12 MAR 2014
- neurexin 1;
Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.
17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.
We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.
No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.