Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: FOXN1

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 2 Feb 2023, 11:32 a.m. | Last Modified: 2 Feb 2023, 11:32 a.m.

Panel Version: 3.4

Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS update. Severe recurrent infections due to T-cell deficiency usually apparent from birth have been associated with both homozygous and heterozygous variants in the FOXN1 gene. Sufficient cases for both inheritance types to rate as Green with this MOI.

Created: 8 Jun 2022, 11:23 a.m. | Last Modified: 8 Jun 2022, 11:23 a.m.

Panel Version: 2.552

IUIS: Inheritance - AR (causes Winged helix nude FOXN1 deficiency. Very low T cells and normal levels of B cells. Decreased Ig. Associated with severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect), AD (causes FOXN1 haploinsufficiency. Severe T cell lymphopenia at birth, usually normalised by adulthood and normal/low levels of B cells. Associated with recurrent, viral and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy).

Created: 8 Jun 2022, 11:15 a.m. | Last Modified: 8 Jun 2022, 11:15 a.m.

Panel Version: 2.551

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green 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, 12:56 p.m. | Last Modified: 14 Oct 2020, 12:56 p.m.

Panel Version: 2.252

The following PubMed IDs were added to gene FOXN1 (OMIM gene MIM#600838): 10206641. 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

• 10206641

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

I don't know

Added publication referenced by IUIS december 2019 update

Created: 28 Feb 2020, 8:49 p.m. | Last Modified: 28 Feb 2020, 8:49 p.m.

Panel Version: 2.36

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): FOXN1 .PanelApp HGNC gene symbol check: FOXN1 . IUIS Disease: Winged helix nudem FOXN1 deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect. 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.

Comment on list classification: Changed from Amber to Green, single variant founder mutation (seen in Italian and Indian populations) but with functional analysis

Created: 18 Jun 2018, 9:38 a.m.

T-cell immunodeficiency, congenital alopecia, and nail dystrophy is a rare disorder, reported majorly in members of a large extended family from a Southern Italian community (PMID:15180707). Two sisters from Italy were the first to be reported with the features of severe combined immunodeficiency (SCID)/NUDE gene (PMID:8911612). Subsequent analysis of 263 Italian families revealed a founder mutation (PMID:11159512). The causative variant was a homozygous nonsense substitution (p.R255X), the resultant protein is likely to lack the DNA binding and transactivation domains resulting in loss-of function.
The FOXN1 p.R255X mutation observed in the PMID: 28636882 (2017) is an ancestral mutation reported in the Italian population. The presence of a homozygous nonsense mutation in FOXN1 gene, the same founder mutation in Italian population, was detected in the present family from South India. Probably, it is attributed to migration of people from the Italian peninsula to India mainly as merchants since Roman times. Functional analysis revealed lack of protein expression in the patients with the homozygous variant.

Created: 18 Jun 2018, 9:35 a.m.

added founder-effect tag

Created: 18 Jun 2018, 9:25 a.m.

Comment on publications: added publications to support FOXN1 loss of function variants cause Nude severe combined immunodeficiency

Created: 18 Jun 2018, 8:59 a.m.

This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Amber. 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: 20 Apr 2018, 10:31 a.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: FOXN1, PanelApp HGNC gene symbol check: FOXN1, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Combined immunodeficiencies / NUDE/SCID / Winged-helix nude deficiency (FOXN1)

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: FOXN1, GRID_Gene_Symbol: FOXN1, GRID_Transcript_ENS_Community submitted: ENST00000226247, GRID_Transcript_RefSeq: NM_003593.2, GRID_Transcript_ENS_used_on_Production: ENST00000226247

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

Publications

• 31447097

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
T-B+ SCID, congenital alopecia, nail dystrophy

Publications

• 15180707
• 10206641
• 21507891

Red List (low evidence)

Comment on list classification: As there is no consensus amoungst reviewers, this gene has been made amber. It is a confirmed DD gene for Alopecia and T-cell immunodeficiency.

Created: 20 May 2016, 2:17 p.m.

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

we are now trying to validate one of these but more CID than classic SCID

Created: 12 Jan 2016, 4:09 p.m.