Clefting

Gene: TBX1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 9:26 a.m. | Last Modified: 11 Oct 2023, 9:26 a.m.

Panel Version: 4.100

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

Green List (high evidence)

Comment on list classification: Following consultation with Helen Brittain (Genomics England Clinical Team) it was agreed that there is sufficient evidence to promote this gene to Green on this panel (at least three cases of palatal involvement) at the next GMS panel update.

Created: 14 Mar 2023, 11:41 a.m. | Last Modified: 14 Mar 2023, 11:41 a.m.

Panel Version: 3.9

TBX1 is encompassed by a region deleted in DiGeorge syndrome (22q11.2). There is some, albeit more limited, evidence linking SNVs with overlapping phenotypes.

Yagi et al 2003 (PMID: 14585638) found three cases with conotruncal anomaly face syndrome or DiGeorge's syndrome including velopharyngeal insufficiency of the cleft palate and/or thymus and parathyroid abnormalities but no cognitive deficits. Zweier et al., 2007 (PMID: 17273972) reported a heterozygous missense variant in a familial case of Shprintzen syndrome and Li et al., 2018 (PMID: 30137364) described two families with splice-altering variants in whom phenotypes ranged from isolated hypoparathyroidism (with reduced penetrance) to hypoparathyroidism with additional DiGeorge sequence-like features.

Also details about an addition case at NWGLH provided by Ronnie Wright on R15 panel. Patient harbouring a de novo final exon frameshift variant referred via immunology clinician and has clinical diagnosis of DiGeorge syndrome (prior 22q11 deletion testing negative).

Created: 14 Mar 2023, 11:36 a.m. | Last Modified: 14 Mar 2023, 11:36 a.m.

Panel Version: 3.6

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

Phenotypes
DiGeorge syndrome, OMIM:188400; Conotruncal anomaly face syndrome, OMIM:217095; Velocardiofacial syndrome, OMIM:192430

Publications

• 14585638
• 17273972
• 30137364

I don't know

Radboud lists mutations in this gene as being linked to the clefting phenotype, as do several literature papers on DiGeorge syndrome, which encompassses cardiac and orofacial clefting phenotypes. However, these mutations are exclusively deletions of 22q11.2, and as the pipeline cannot currently cater for larger SVs, this gene is amber.

Created: 31 May 2017, 3:30 p.m.

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

Phenotypes
CONOTRUNCAL HEART MALFORMATIONS; CTHM