Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: TBX1

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 12:54 p.m. | Last Modified: 11 Oct 2023, 12:54 p.m.

Panel Version: 4.37

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 immune 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: 3.8

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, 11:33 a.m. | Last Modified: 14 Mar 2023, 11:33 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

Green List (high evidence)

NHSE Genomic Medicine service - NWGLH (contact lab for case details if required): de novo tier 3 TBX1 final exon frameshift in a patient referred via immunology clinician and has clinical diagnosis of DiGeorge syndrome (prior 22q11 deletion testing negative) - absent thymus, low T-Cells, recurrent infections... also hypoparathyroidism, hypocalcaemia, velopharangeal anomalies. Had this patient been referred as singleton the TBX1 variant may not have been prioritised for review. Unclear why 22q11 deletion region is included as green for immunology panel (because it may be the syndromic cause for immunodeficiency) but TBX1 is not. Is this sufficient evidence to upgrade TBX1 to Green on this panel for DiGeorge syndrome phenotype or is the expectation for immunologists to add alternative panel (where it is rated Green and causative of DiGeorge syndrome)?

Created: 8 Dec 2022, 8:56 a.m. | Last Modified: 8 Dec 2022, 8:56 a.m.

Panel Version: 3.1

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.

Created: 14 Oct 2020, 12:17 p.m. | Last Modified: 14 Oct 2020, 12:17 p.m.

Panel Version: 2.216

The following PubMed IDs were added to entity TBX1: 12548732. These publications have been associated with OMIM phenotype MIM#188400, which is listed for this entity, by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Comment on list classification: After consultation with the Genomics England clinical team, keeping this gene as Amber. Further evidence is needed for the role of SNVs in TBX1 contributing to the PID phenotype.

Created: 19 Jun 2018, 9:35 a.m.

Comment on phenotypes: Added MIM identifier for DiGeorge Syndrome

Created: 14 Jun 2018, 2:16 p.m.

Comment on publications: Added publications relating to TBX1 variants and phenotypes

Created: 14 Jun 2018, 2:15 p.m.

In OMIM TBX1 is associated with DiGeorge Syndrome. Immunodeficiency is a clinical feature of this syndrome (Davies 2013 (PMID: 24198816)). Davies report that in 90% of cases of DiGeorge Syndrome have a typical 3 Mb deletion including over 30 different genes. There is some evidence that TBX1 is associated with the immunodeficiency phenotype. Yagi et al 2013 (PMID: 14585638) report on 13 patients from ten families who have the 22q11.2 syndrome phenotype (which includes DiGeorge Syndrome) but no detectable deletion of 22q11.2. Three new point mutations of TBX1 were discovered. These three mutations were not observed in 1110 normal, unrelated control chromosomes. Patient F2, with a point mutation resulting in a non-synonymous change G310S was diagnosed with DiGeorge's syndrome and his clinical phenotype included absent thymus suggesting a role for TBX1 in this phenotype. Jerome and Papaioannou, 2001 (PMID: 11242110) report that Tbx1-/- mice display a wide range of developmental anomalies including hypoplasia of the thymus. Overall there is not a strong degree of evidence from the literature that TBX1 variants alone are responsible for an immunodeficiency phenotype.

Created: 14 Jun 2018, 2:06 p.m.

Publications

• 12548732

I don't know

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TBX1 .PanelApp HGNC gene symbol check: TBX1 . IUIS Disease: TBX1 deficiency . IUIS Inheritance: AD .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: Thymic Defects with Additional Congenital Anomalies

Created: 2 Jul 2018, 10:35 a.m.

This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Red. The gene is present in the external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 19 Apr 2018, 1:30 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: Del 22q11.2, PanelApp HGNC gene symbol check: TBX1, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Combined immunodeficiencies / Severe combined immunodeficiency (SCID) / Severe combined immunodeficiency (SCID); Other well defined PIDs / DiGeorge syndrome / DiGeorge syndrome

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TBX1, GRID_Gene_Symbol: TBX1, GRID_Transcript_ENS_Community submitted: ENST00000332710, GRID_Transcript_RefSeq: NM_080647.1, GRID_Transcript_ENS_used_on_Production: ENST00000332710

Created: 17 Apr 2018, 12:12 p.m.

Red List (low evidence)

Red List (low evidence)

Comment on list classification: After reviewer ratings and comments, this should remain on the red list for now.

Created: 20 May 2016, 2:21 p.m.

I don't know

I would chose amber, we have seen it in several patients and functional as well as immunological data suggests real (patient lacks thymus but not 22q by array, missense mutation identified), but haven't published so at the moment the data isn't there.

Created: 20 Oct 2015, 1:47 p.m.

Red List (low evidence)

TBX1 is among the genes in the region 22q11.21 deleted in di George syndrome, which sometimes causes SCID. The aetiologic role of TBX1 in this phenotype is not known. OMIM provides a specific ID for di George syndrome, 188400

Created: 19 Oct 2015, 8:03 p.m.