RT Journal Article SR Electronic T1 Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 90 OP 97 DO 10.1136/jmedgenet-2013-102001 VO 51 IS 2 A1 A V Postma A1 M Alders A1 M Sylva A1 C M Bilardo A1 E Pajkrt A1 R R van Rijn A1 S Schulte-Merker A1 S Bulk A1 S Stefanovic A1 A Ilgun A1 P Barnett A1 M M A M Mannens A1 A F M Moorman A1 R J Oostra A1 M C van Maarle YR 2014 UL http://jmg.bmj.com/content/51/2/90.abstract AB Background The T gene (brachyury gene) is the founding member of the T-box family of transcription factors and is vital for the formation and differentiation of the mesoderm and the axial development of all vertebrates. Results We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies, and the identification and characterisation of their underlying genetic defect. Given the consanguineous nature and the similarity of the phenotypes between the three families, we performed homozygosity mapping and identified a common 4.1 Mb homozygous region on chromosome 6q27, containing T, brachyury homologue (mouse) or T. Sequencing of T in the affected individuals led to the identification of a homozygous missense mutation, p.H171R, in the highly conserved T-box. The homozygous mutation results in diminished DNA binding, increased cell growth, and interferes with the normal expression of genes involved in ossification, notochord maintenance and axial mesoderm development. Conclusions We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.