Skeletal dysplasia

Gene: TBX6

Green List (high evidence)

108 Chinese CVM cases identified 10 (9.3%) carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. Similar phenotype observed in mice with combined null and hypomorphic alleles of Tbx6 (PMID: 30307510)

200 patients with Congenital scoliosis (CS) or Spondylocostal dysostosis (SCD) were investigated for TBX6 variants. Five 16p11.2 deletions, one splice-site variant and five missense variants were identified in 10 patients. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Functional studies showed mislocalisation. Conclusion - Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis (PMID: 31015262)

Evidence for association between mono-allelic variants and disease is limited.

Created: 13 Nov 2020, 7:55 a.m. | Last Modified: 13 Nov 2020, 7:55 a.m.

Panel Version: 0.61

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondylocostal dysostosis 5, 122600

Publications

• 33058178
• 31015262
• 30636772
• 28054739
• 23335591
• 30307510

Comment when marking as ready: Biallelic variants associated with spondylocostal dysostosis in >3 unrelated individuals
Mouse model recapitulates phenotype

Created: 20 Apr 2020, 5:31 a.m. | Last Modified: 20 Apr 2020, 5:31 a.m.

Panel Version: 0.2418

Green List (high evidence)

108 Chinese CVM cases identified 10 (9.3%) carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. Similar phenotype observed in mice with combined null and hypomorphic alleles of Tbx6 (PMID: 30307510)

200 patients with Congenital scoliosis (CS) or Spondylocostal dysostosis (SCD) were investigated for TBX6 variants. Five 16p11.2 deletions, one splice-site variant and five missense variants were identified in 10 patients. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Functional studies showed mislocalisation. Conclusion - Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis (PMID: 31015262)

Created: 20 Apr 2020, 4:34 a.m. | Last Modified: 20 Apr 2020, 4:34 a.m.

Panel Version: 0.2377

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
congenital vertebral malformations, congenital scoliosis, spondylocostal dysostosis

Publications

• PMID: 30307510
• 31015262

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

>3 families with SPONDYLOCOSTAL DYSOSTOSIS 5. Bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Created: 20 Apr 2020, 3:35 a.m. | Last Modified: 20 Apr 2020, 3:35 a.m.

Panel Version: 0.2365

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Skeletal dysplasia; spondylocostal dysostosis; congenital scoliosis

Publications

• 8954725
• 20503311
• 23335591
• 25564734
• 31015262

Variants in this GENE are reported as part of current diagnostic practice