Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6

Sparrow, Duncan B., McInerney-Leo, Aideen, Gucev, Zoran S., Gardiner, Brooke, Marshall, Mhairi, Leo, Paul J., Chapman, Deborah L., Tasic, Velibor, Shishko, Abduhadi, Brown, Matthew A., Duncan, Emma L. and Dunwoodie, Sally L. (2013) Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Human Molecular Genetics, 22 8: 1625-1631. doi:10.1093/hmg/ddt012

Author Sparrow, Duncan B.
McInerney-Leo, Aideen
Gucev, Zoran S.
Gardiner, Brooke
Marshall, Mhairi
Leo, Paul J.
Chapman, Deborah L.
Tasic, Velibor
Shishko, Abduhadi
Brown, Matthew A.
Duncan, Emma L.
Dunwoodie, Sally L.
Title Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6
Formatted title
Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2013-04-15
Year available 2013
Sub-type Article (original research)
DOI 10.1093/hmg/ddt012
Open Access Status
Volume 22
Issue 8
Start page 1625
End page 1631
Total pages 7
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2014
Language eng
Formatted abstract
In humans, congenital spinal defects occur with an incidence of 0.5–1 per 1000 live births. One of the most
severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic
basis of several forms of autosomal recessive SCD cases has been solved with the identification of four
causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been
reported, but to date no genetic etiology has been described for these. Here, we have used exome capture
and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in
two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation
activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning
of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in
this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and
also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases
even in small families with few affected individuals.
Keyword Mouse Embryos
Segmentation Defects
Presomitic Mesoderm
Paraxial Mesoderm
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes First published online January 17 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 20 times in Thomson Reuters Web of Science Article | Citations
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