Primary immunodeficiency or monogenic inflammatory bowel disease
Gene: TFRC
Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.
Although this variant is found in a homozygous region that is shared between two different families from different geographic regions reported in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.
The 'founder-effect' tag has also been added to highlight this.Created: 1 Nov 2023, 4:05 p.m. | Last Modified: 1 Nov 2023, 4:16 p.m.
Panel Version: 4.83
PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls.
The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor.
Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts.
In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype.
PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life.
This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel).Created: 1 Nov 2023, 11:12 a.m. | Last Modified: 1 Nov 2023, 3:58 p.m.
Panel Version: 4.80
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Immunodeficiency 46, OMIM:616740
Publications
PMID: 32851577 reported 8 new patients (from 6 different families), all from Arab backgrounds. All had the same homozygous variant as previously reportedCreated: 13 Oct 2023, 10:48 a.m. | Last Modified: 13 Oct 2023, 10:48 a.m.
Panel Version: 4.41
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Immunodeficiency 46
Publications
The following PubMed IDs were added to entity TFRC: 26642240. These publications have been associated with OMIM phenotype MIM#616740, 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
Publications
Comment on list classification: Promoted from Red to Amber based on expert review and evidence.Created: 15 Apr 2020, 3:42 p.m. | Last Modified: 15 Apr 2020, 3:42 p.m.
Panel Version: 2.81
Single family and functional data.Created: 11 Apr 2020, 11:06 a.m. | Last Modified: 11 Apr 2020, 11:06 a.m.
Panel Version: 2.51
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Immunodeficiency 46, MIM# 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia
Publications
OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TFRC .PanelApp HGNC gene symbol check: TFRC . IUIS Disease: TFRC deficiency . IUIS Inheritance: AR .T cells: Decreased, .B cells: Nl number, low memory B cells, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent infections, neutropenia, thrombocytopenia. IUIS Major category: Immunodeficiencies affecting cellular and humoral immunity. IUIS Subcategory: Combined Immunodeficiencies Generally Less Profound than Severe Combined ImmunodeficiencyCreated: 6 Jul 2018, 12:24 p.m.
Phenotypes for gene: TFRC were changed from Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity; Immunodeficiency 46, 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia to Immunodeficiency 46, OMIM:616740
Publications for gene: TFRC were set to 32086639; 26642240; 32048120
Gene: tfrc has been classified as Amber List (Moderate Evidence).
Tag founder-effect tag was added to gene: TFRC.
Tag Q4_23_promote_green tag was added to gene: TFRC. Tag Q4_23_NHS_review tag was added to gene: TFRC.
Source Other was added to TFRC. Publications for gene TFRC were updated from 32048120; 32086639; 26642240 to 32086639; 26642240; 32048120
Gene: tfrc has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: TFRC were changed from Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity to Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity; Immunodeficiency 46, 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia
Publications for gene: TFRC were set to 32048120; 32086639
Source IUIS Classification December 2019 was added to TFRC. Mode of inheritance for gene TFRC was changed from to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity for gene: TFRC Publications for gene TFRC were updated from to 32048120; 32086639
2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.
Phenotypes for gene TFRC were set to Recurrent infections, neutropenia, thrombocytopenia, Immunodeficiencies affecting cellular and humoral immunity
TFRC was added to Primary immunodeficiency disorders panel. Sources: IUIS Classification February 2018
TFRC was created by Louise Daugherty