Spondylocostal Dysostosis

Gene: TBX6

Green List (high evidence)

OMIM lists the phenotype as AD and AR, but reports for AD are dubious.
A very common hypomorphic haplotype found in 32% of the global population is found very commonly in trans (gnomAD, PMID: 31015262, PMID: 33058178).

PMID: 28054739: describes AD segregating families with protein elongation variants, but later says all affecteds had the risk haplotype in trans. Mother carrier of elongation variant only – NORMAL.
PMID: 23335591: elongation variant segregated as AD in a family. PMID: 28054739 notes only a single patient in this family lacked the haplotype in trans, suspects an additional variant may be present consistent with AR inheritance.

PMID: 30636772: All patients (>48) with congenital scoliosis had the haplotype in trans. Notes human hypomorphic haplotype has ~70% activity (Fig S8), mouse equivalent has ~65% activity.
-Only mouse model -/mh (biallelic null/mild hypomorphic) had vertebral malformations. Het mice (wt/mh), (wt/-) and hom hypomorphic (mh/mh) were phenotypically normal (Table S3).
PMID: 28054739: Studied protein elongation variants and shows cotransfection with wildtype maintained reduced enzyme activity -> DN.
PMID: 23335591: Protein elongation variant - no significant reduction to wildtype when cotransfected with mutant protein -> NO DN

Whole gene deletion is very commonly reported, with an estimated global frequency of 0.03% (Takeda 2017)

Summary: no solid evidence of AD inheritance. Initially suspicious for protein elongation variants but appears most patients have the risk haplotype in trans, with carriers reported as both normal or affected. Loss of function is very much the only established mechanism for this gene.

Created: 13 Nov 2020, 3:35 a.m. | Last Modified: 13 Nov 2020, 3:35 a.m.

Panel Version: 0.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondylocostal dysostosis 5, 122600

Publications

• PMID: 33058178
• 31015262
• 30636772
• 28054739
• 23335591