Spondylocostal Dysostosis via the TBX6 Gene

Congenital vertebral malformation (CVM) is a birth defect of the vertebral column with an estimated prevalence 0.13-0.51 per 1000 live births (Giampietro et al. 2009. PubMed ID: 19154516). It can be further divided into several groups such as Klippel-Feil syndrome and Spondylocostal Dysostosis. Fetal ultrasound can detect vertebrae defects as early as 13 weeks' gestation (Turnpenny et al. 2017. PubMed ID: 20301771).

Spondylocostal Dysostosis (SCD) involves segmentation defect(s) of the vertebrae. Patients with SCD have short trunks with multiple vertebral defects and rib anomalies (Turnpenny et al. 2017. PubMed ID: 20301771). SCD is further divided into six sub-groups caused by pathogenic variants in the DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2 genes, respectively.

Molecular genetic testing is advantageous to establish a proper diagnosis for individuals with CVM or SCD.

Pathogenic variants in the TBX6 gene have been reported in several patients with autosomal recessive and dominant SCD, with autosomal recessive predominating (Lefebvre et al. 2017. PubMed ID: 27861764; Turnpenny et al. 2017 PubMed ID: 20301771; Sparrow et al. 2013. PubMed ID: 23335591). The 16p11.2 deletion involving TBX6 has been repeatedly reported in patients with congenital scoliosis (Wu et al. 2015. PubMed ID: 25564734; Al-Kateb et al. 2014. PubMed ID: 24458548; Takeda et al. 2017. PubMed ID: 28054739). In one study, a proximal 16p11.2 deletion involving TBX6 in the compound heterozygous state along with a common risk haplotype was found in 11% of studied sporadic congenital scoliosis cases (Wu et al. 2015. PubMed ID: 25564734). In addition, in 2 of 20 trios studied the deletion occurred de novo. Pathogenic variants in the TBX6 gene contribute to ~10% of SCD cases (Turnpenny et al. 2017 PubMed ID: 20301771).

The TBX6 protein, coded by the TBX6 gene, is a regulator for Notch signal pathway and a member of the T-box DNA-binding domain family. TBX6 plays an essential role in embryonic neural plate and somite development (Chapman and Papaioannou. 1998. PubMed ID: 9490412; O'Roak et al. 2012. PubMed ID: 22495309). Mice with absence of TBX6 die around embryonic day 10.5, and mice with heterozygous TBX6 null alleles present vertebral defects with incomplete penetrance (Sparrow et al. 2013. PubMed ID: 23335591). To date, ~ 20 potential causative variants in TBX6 have been documented in Human Gene Mutation Database (HGMD). They include missense, nonsense, splicing, and small frameshift deletions/duplications. Of note, the 16p11.2 deletion or duplication involving TBX6 has also been reported to be associated with several other conditions such as autism spectrum disorders, and congenital anomalies of the kidney and urinary tract. The deletions/duplications were reported to be de novo in some of these cases (O'Roak et al. 2012. PubMed ID: 22495309; Verbitsky et al. 2019. PubMed ID: 30578417).

Pathogenic variants in the TBX6 gene contribute to ~10% of SCD cases (Turnpenny et al. 2017 PubMed ID: 20301771).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the TBX6 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).