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Original article
De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder
  1. Christian Babbs1,2,
  2. Deborah Lloyd1,
  3. Alistair T Pagnamenta2,3,
  4. Stephen R F Twigg1,
  5. Joanne Green1,
  6. Simon J McGowan1,
  7. Ghazala Mirza3,
  8. Rebecca Naples1,
  9. Vikram P Sharma1,4,
  10. Emanuela V Volpi3,
  11. Veronica J Buckle1,
  12. Steven A Wall4,
  13. Samantha J L Knight2,3,
  14. International Molecular Genetic Study of Autism Consortium (IMGSAC),
  15. Jeremy R Parr5,
  16. Andrew O M Wilkie1,2,4
  1. 1Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
  2. 2NIHR Biomedical Research Centre, Oxford, UK
  3. 3Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  4. 4Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK
  5. 5Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK
  1. Correspondence to Prof Andrew O M Wilkie, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK, OX3 9DS, UK; andrew.wilkie{at} Dr Jeremy R Parr, Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK;


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.

  • Genetics
  • Molecular genetics
  • Chromosomal
  • Clinical genetics
  • Psychiatry

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:

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