Lookup NU author(s): Professor Jeremy Parr
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ~70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. Methods: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). Results: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. Conclusions: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosagesensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.
Author(s): Babbs C, Lloyd D, Pagnamenta AT, Twigg SRF, Green J, McGowan SJ, Mirza G, Naples R, Sharma VP, Volpi EV, Buckle VJ, Wall SA, Knight SJL, Parr JR, Wilkie AOM
Publication type: Article
Publication status: Published
Journal: Journal of Medical Genetics
Print publication date: 01/11/2014
Online publication date: 14/10/2014
Acceptance date: 13/08/2014
Date deposited: 23/11/2017
ISSN (print): 0022-2593
ISSN (electronic): 1468-6244
Publisher: BMJ Publishing Group
PubMed id: 25228304
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