Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CD8A

I don't know

PMID: 26563160 reported a third patient with this disorder. From consanguineous Portuguese family, with same homozygous variant as previously reported. Not sure whether this is enough to push gene into green category (as same variant, and Portuguese vs Spanish Gypsy heritage)
PMID mentioned below, but not sure if taken into account as no reference to contents of paper

Created: 18 Oct 2023, 11:02 a.m. | Last Modified: 18 Oct 2023, 11:03 a.m.

Panel Version: 4.50

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
CD8 deficiency familial, 608957

Publications

• 26563160

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

Panel Version: 2.211

The following PubMed IDs were added to gene CD8A (OMIM gene MIM#186910): 17658607;26563160;11435463. These publications have been associated with the gene 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

• 17658607
• 26563160
• 11435463

I don't know

I don't know

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CD8A .PanelApp HGNC gene symbol check: CD8A . IUIS Disease: CD8 deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent infections, may be asymptomatic. IUIS Major category: Immunodeficiencies affecting cellular and humoral immunity. IUIS Subcategory: Combined Immunodeficiencies Generally Less Profound than Severe Combined Immunodeficiency

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

Keep amber after external expert review until more info on gene and disease association

Created: 27 Jun 2018, 7:13 p.m.

Kept Amber to Green after internal clinical review, it was noted that there is a single variant in a single population without any functional work up to support this variant or the mechanism. Feeding back all rare variants in this gene currently would not seem to beneficial, in particular when the Immunologists would be able to identify isolated CD8+ lymphocyte deficiency through their work up (T cell subset testing). Keep Amber until further evidence on gene/variants.

Created: 15 Jun 2018, 9:50 a.m.

Past onto clinical team for further discussion. Our current PanelApp rules denote that for a founder mutation we cannot make these genes Green. There are exceptions to this rule (reviewed by clinical team) if there has been an additional pathogenic var. conformed/reported. In this instance there is currently only one mutation that gives rise to observed PID phenotype.

Created: 11 Jun 2018, 2:19 p.m.

added founder -effect tag

Created: 11 Jun 2018, noon

Comment on publications: de la Calle-Martin et al. (2001) PMID: 11435463 described a patient of Spanish-gyypsy origin with recurrent bacterial and viral infections and total absence of CD8-positive T cells, and identified a homozygous 331G-A transition in the CD8A gene, resulting in a gly90-to-ser (G90S) substitution in a conserved residue in the immunoglobulin domain of the protein.
Mancebo E et al. (2008) PMID:17658607 describes the second case for CD8 immunodeficiency confirming the pathogenic effect of p.Gly111Ser, the same variant as previously reported by de la Calle-Martin et al. (2001). Looking at 1127 unrelated control individuals: 734 subjects of Gypsy ancestry from different sub-isolates and geographic locations in Europe, and 393 of Spanish (non-Gypsy) ethnicity. The result indicated that p.Gly111Ser is confined to the Spanish Gypsy population, where it occurs at a carrier rate of 0.4%. Analysis of microsatellite markers flanking the CD8A mutated gene revealed a shared polymorphic haplotype suggesting a common founder for p.Gly111Ser mutation that causes CD8 deficiency in the Spanish Gypsy population. CD8 immunodeficiency should be given diagnostic consideration in Spanish Gypsies with recurrent infections.

Created: 11 Jun 2018, 11:49 a.m.

Comment on phenotypes: added phenotype from Orphanet and OMIN MIMid. Susceptibility to respiratory infections associated with CD8 alpha chain mutation is a rare primary immunodeficiency due to a defect in adaptive immunity characterized by the absence of CD8+ T cells with normal immunoglobulin and specific antibody titres in blood and susceptibility to recurrent respiratory bacterial and viral infections. Symptom severity range from fatal respiratory insufficiency to mild or asymptomatic phenotypes.

Created: 11 Jun 2018, 10:27 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in 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: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: CD8A, PanelApp HGNC gene symbol check: CD8A, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Combined immunodeficiencies / CD8-deficiency / CD8 deficiency

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CD8A, GRID_Gene_Symbol: CD8A, GRID_Transcript_ENS_Community submitted: ENST00000409511, GRID_Transcript_RefSeq: NM_001768.6, GRID_Transcript_ENS_used_on_Production: ENST00000409511

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