title: Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6.
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.
authors: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors: Duncan B
authors: DB
authors: Sparrow
authors: Aideen
authors: A
authors: McInerney-Leo
authors: Zoran S
authors: ZS
authors: Gucev
authors: Brooke
authors: B
authors: Gardiner
authors: Mhairi
authors: M
authors: Marshall
authors: Paul J
authors: PJ
authors: Leo
authors: Deborah L
authors: DL
authors: Chapman
authors: Velibor
authors: V
authors: Tasic
authors: Abduhadi
authors: A
authors: Shishko
authors: Matthew A
authors: MA
authors: Brown
authors: Emma L
authors: EL
authors: Duncan
authors: Sally L
authors: SL
authors: Dunwoodie
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D004195:Disease Models, Animal; D005799:Genes, Dominant; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D006548:Hernia, Diaphragmatic / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D009154:Mutation; D010375:Pedigree; D011859:Radiography; D017422:Sequence Analysis, DNA; D019170:Somites / Q000254:growth & development / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020825:T-Box Domain Proteins; C491182:TBX6 protein, human