Skeletal dysplasia

Gene: TBX6

Green List (high evidence)

TBX6 is associated with spondylocostal dysostosis 5 (SCDO5) (OMIM: 122600; accessed August 2026). 17 heterozygous TBX6 null mutations were identified in congenital scoliosis patients, comprising copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and null variants (1 nonsense, 4 frameshift). Segregation demonstrated that a null allele alone was insufficient to cause congenital scoliosis (16p11.2 deletion carriers without the risk allele were radiologically normal). A common TBX6 hypomorphic/ risk haplotype (T-C-A comprising non-reference SNPs rs2289292, rs3809624 and rs3809627) was identified as the second allele in all 17 null-mutation carriers, and this compound inheritance was validated in a further 5 congenital scoliosis patients (Wu et al. 2015, PMID 25564734). The T-C-A risk allele was found to reduce TBX6 expression, suggesting a mechanism whereby the TBX6 hypomorphic/ risk allele is required to reduce gene-expression dosage beyond haploinsufficiency for penetrance of the congenital scoliosis phenotype (Wu et al. 2015, PMID 25564734).

Homozygous c.1148C>A p.Ser383Ter was identified in a fetus with a very severe presentation; complete NMD is unlikely (final exon truncation), and RT-PCR showed reduced TBX6 expression in both parents to some degree, pointing to transcript instability (Errichiello et al. 2020, PMID 33058178).

Autosomal dominant SCDO was identified in a three-generation family, with widespread vertebral malformations, relative sparing of rib involvement, and mild scoliosis. Heterozygous TBX6 c.1311A>T p.(Ter437CextTer81) which disrupted the canonical stop and added 81 amino acids to the C terminus, segregated with the condition, and functional studies showed reduced transcriptional activity (roughly half that of the WT allele) (Sparrow et al. 2013, PMID 23335591; Wu et al. 2015, PMID 25564734). Subsequent analysis placed this stop-loss variant within the T-C-A risk haplotype.

Conclusion: SCDO5 follows a complex compound inheritance pattern, typically requiring a loss-of-function TBX6 allele in trans with a common hypomorphic risk haplotype that further reduces TBX6 expression below the threshold required for normal vertebral development. Isolated cases showing apparent autosomal dominant inheritance have been described. Following clinical discussion, an MOI of both monoallelic and biallelic was deemed appropriate based on biological and technical factors. Upon identification of a single heterozygous TBX6 LoF variant, additional manual examination of rs2289292, rs3809624 and rs3809627 (all of which have high population frequencies in isolation) followed by parental phasing may be necessary to establish or exclude a genetic diagnosis of TBX6-related disease. Thus, a single tiered TBX6 LoF variant should not be considered a simple carrier finding by default in a patient with a consistent phenotype.

Created: 8 Sep 2026, 10:55 a.m. | Last Modified: 8 Sep 2026, 10:55 a.m.

Panel Version: 10.8

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Spondylocostal dysostosis 5 (OMIM #122600); spondylocostal dysostosis 5 (MONDO:0007389)

Publications

• PIMD: 25564734
• 33058178
• 23335591

Green List (high evidence)

characterized clinically by: a short trunk in proportion to height; Dysostoses with predominant vertebral with and without costal involvement gp of SD. Several cases; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spondylocostal dysostosis 5 122600

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: TBX6; Initial rating suggestion: green

Created: 6 Mar 2019, 11:37 a.m.

Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)

Created: 21 Jun 2016, 1:13 p.m.

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:08 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spondylocostal dysostosis 5 122600

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