Journal Article

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

Oostra, R J, Sylva, M, Moorman, A F M, Stefanovic, S, Bilardo, C M, Schulte-Merker, S, Pajkrt, E, Bulk, S, van Rijn, R R, Ilgun, A, Alders, M, Barnett, P, Postma, A V, van Maarle, M C, Mannens, M M A M

2014

Overview

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.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Abnormalities, Multiple - diagnostic imaging / Abnormalities, Multiple - genetics / Abnormalities, Multiple - mortality / Amino Acid Sequence / Base Sequence / Cell Line, Tumor / Cell Proliferation / Chromosomes, Human, Pair 6 - genetics / Clinical Genetics / Comparative Genomic Hybridization / Consanguinity / Developmental / Female / Fetal Proteins - genetics / Genetic Association Studies / Genetic testing / Genetics & genetic processes / Genome-Wide / Genomes / Génétique & processus génétiques / Homozygote / Humans / Infant / Infant, Newborn / Life sciences / Linkage / Localization / Male / Mutagenesis / Mutation / Mutation, Missense / Notochord - abnormalities / Notochord - diagnostic imaging / Ossification, Heterotopic - diagnostic imaging / Ossification, Heterotopic - genetics / Ossification, Heterotopic - mortality / Pedigree / Protein Binding / Protein Transport / Proteins / Sacrum - abnormalities / Sacrum - diagnostic imaging / Sciences du vivant / Spine - abnormalities / Spine - diagnostic imaging / Syndrome / T-Box Domain Proteins - genetics / Ultrasonography, Prenatal