De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder

Christian Babbs, Deborah Lloyd, Alistair T. Pagnamenta, Stephen R F Twigg, Joanne Green, Simon J. McGowan, Ghazala Mirza, Rebecca Naples, Vikram P. Sharma, Emanuela V. Volpi, Veronica J. Buckle, Steven A. Wall, Samantha J L Knight, Jeremy R. Parr, Andrew O M Wilkie, International Molecular Genetic Study of Autism Consortium (IMGSAC)

Research output: Contribution to journalArticle

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Abstract

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.

LanguageEnglish
Pages737-747
Number of pages11
JournalJournal of Medical Genetics
Volume51
Issue number11
DOIs
StatusPublished - 2014

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Mutation
Chromosomes, Human, Pair 22
Missense Mutation
Autistic Disorder
Intellectual Disability
Molecular Biology
Chromosome Breakpoints
Exome
Autism Spectrum Disorder
Mosaicism
Southern Blotting
Fluorescence In Situ Hybridization
Cytogenetics
Introns
Open Reading Frames
Siblings
Exons
Phenotype
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Babbs, C., Lloyd, D., Pagnamenta, A. T., Twigg, S. R. F., Green, J., McGowan, S. J., ... International Molecular Genetic Study of Autism Consortium (IMGSAC) (2014). De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder. Journal of Medical Genetics, 51(11), 737-747. https://doi.org/10.1136/jmedgenet-2014-102582

De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder. / Babbs, Christian; Lloyd, Deborah; Pagnamenta, Alistair T.; Twigg, Stephen R F; Green, Joanne; McGowan, Simon J.; Mirza, Ghazala; Naples, Rebecca; Sharma, Vikram P.; Volpi, Emanuela V.; Buckle, Veronica J.; Wall, Steven A.; Knight, Samantha J L; Parr, Jeremy R.; Wilkie, Andrew O M; International Molecular Genetic Study of Autism Consortium (IMGSAC).

In: Journal of Medical Genetics, Vol. 51, No. 11, 2014, p. 737-747.

Research output: Contribution to journalArticle

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 & International Molecular Genetic Study of Autism Consortium (IMGSAC) 2014, 'De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder', Journal of Medical Genetics, vol. 51, no. 11, pp. 737-747. https://doi.org/10.1136/jmedgenet-2014-102582
Babbs, Christian ; Lloyd, Deborah ; Pagnamenta, Alistair T. ; Twigg, Stephen R F ; Green, Joanne ; McGowan, Simon J. ; Mirza, Ghazala ; Naples, Rebecca ; Sharma, Vikram P. ; Volpi, Emanuela V. ; Buckle, Veronica J. ; Wall, Steven A. ; Knight, Samantha J L ; Parr, Jeremy R. ; Wilkie, Andrew O M ; International Molecular Genetic Study of Autism Consortium (IMGSAC). / De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder. In: Journal of Medical Genetics. 2014 ; Vol. 51, No. 11. pp. 737-747.
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abstract = "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.",
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T1 - De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder

AU - Babbs, Christian

AU - Lloyd, Deborah

AU - Pagnamenta, Alistair T.

AU - Twigg, Stephen R F

AU - Green, Joanne

AU - McGowan, Simon J.

AU - Mirza, Ghazala

AU - Naples, Rebecca

AU - Sharma, Vikram P.

AU - Volpi, Emanuela V.

AU - Buckle, Veronica J.

AU - Wall, Steven A.

AU - Knight, Samantha J L

AU - Parr, Jeremy R.

AU - Wilkie, Andrew O M

AU - International Molecular Genetic Study of Autism Consortium (IMGSAC)

PY - 2014

Y1 - 2014

N2 - 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.

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 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.

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