RT Journal Article SR Electronic T1 De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 737 OP 747 DO 10.1136/jmedgenet-2014-102582 VO 51 IS 11 A1 Christian Babbs A1 Deborah Lloyd A1 Alistair T Pagnamenta A1 Stephen R F Twigg A1 Joanne Green A1 Simon J McGowan A1 Ghazala Mirza A1 Rebecca Naples A1 Vikram P Sharma A1 Emanuela V Volpi A1 Veronica J Buckle A1 Steven A Wall A1 Samantha J L Knight A1 International Molecular Genetic Study of Autism Consortium (IMGSAC) A1 Jeremy R Parr A1 Andrew O M Wilkie YR 2014 UL http://jmg.bmj.com/content/51/11/737.abstract AB 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 dosage-sensitive 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.