Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: NFAT5

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.

Created: 30 Oct 2023, 5:45 p.m. | Last Modified: 30 Oct 2023, 5:45 p.m.

Panel Version: 4.64

PMID:25667416 - A young male with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. He was identified with 559kb deletion at 16q22.1, which contained eight genes including NFAT5 and this deletion was de novo. Inhibition or deletion of NFAT5 in normal human and murine cells also recapitulated several of the immune deficits identified in the patient.

PMID:36238298 - Two paediatric Mexican patients were identified with rare heterozygous missense variants (individual 1: c.335C>T/ p.Ser112Phe or p.Ser94Phe; individual 2: c.1291A>T/ p.Thr431Ser) and reported with Epstein-Barr virus susceptibility. One patient had chronic active EBV infection with hepatitis and enterocolitis, and the other had fatal hemophagocytic lymphohistiocytosis (HLH).

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.

Created: 30 Oct 2023, 5:44 p.m. | Last Modified: 30 Oct 2023, 5:44 p.m.

Panel Version: 4.61

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 25667416
• 36238298

Green List (high evidence)

PMID: 36238298 describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis
In the discussion, they also refer to other, unpublished patients:
"Some other patients from Belarus, Ukraine, and the USA, with NFAT5 haploinsufficiency caused by heterozygous missense or small deletion variants, manifest early in life with diverse autoimmune diseases, and their T cells show reduced proliferation and survival under hypertonic conditions (Svetlana Sharapova, personal communication)"

Created: 24 Oct 2023, 8:32 a.m. | Last Modified: 24 Oct 2023, 8:32 a.m.

Panel Version: 4.53

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
NFAT5 haploinsufficiency

Publications

• 36238298

The following PubMed IDs were added to gene NFAT5 (OMIM gene MIM#604708): 25667416. These publications have been associated with the gene by the immunedysregulation 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

• 25667416

Red List (low evidence)

One case only described

Created: 29 Jun 2018, 2:51 p.m.

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 3 May 2024, 8:36 p.m. | Last Modified: 3 May 2024, 8:36 p.m.

Panel Version: 5.3

Comment on list classification: This rating of this gene has been returned to red. The amber rating was made in error as only one immunodeficiency associated variant has been reported in this gene.

Created: 26 Sep 2018, 2:30 p.m.

Not associated with a phenotype in OMIM or in Gen2Phen. No variants reported, however, haploinsufficiency of NFAT5 was reported in young man with autoimmune enterocolopathy and unexplained infections revealing evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells (PMID 25667416).
NFAT5 is one of 8 genes (NFAT5, MIR1538, NQO1, NOB1, WWP2, MIR140, CLEC18A, and PDXDC2) located in a 559-kilobase deletion within 16q22.1 (PMID 25667416), none of the other genes appear to have any association with immunodeficiency and are not listed on this panel.
Based on this evidence in consultation with Helen Britain (Clinical Fellow, Genomics England), this gene has been promoted to amber, with a "watchlist" tag applied as it appears that changes in this gene could potentially be relevant to this panel.

Created: 2 May 2018, 1:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

watch tag added - there is supportive evidence in terms of cellular studies in mice that partially reproduce the immune phenotype with haploinsufficiency of this gene, Watchlist tag added in relation for further evidence of CNV / SNVs to promote it to green.

Created: 26 Sep 2018, 2:37 p.m.

Comment on list classification: Changed from Amber to Red. Only one published case with immunodeficiency to date. Gene is pertinent on Victorian Clinical Genetics Services panel and GRID for Immunological disorders. Request evidences from Victorian Clinical Genetics Services and GRID.

Created: 4 Jul 2018, 4:03 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): NFAT5 .PanelApp HGNC gene symbol check: NFAT5 . IUIS Disease: NFAT5 haploinsufficiency . IUIS Inheritance: AD .T cells: CD8 and CD4 T cells may be decreased, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: IBD, recurrent sinopulmonary infections. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Immune Dysregulation with Colitis

Created: 2 Jul 2018, 10:35 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 supplied by GRID. GRID Gene Symbol HGNC PanelApp check: NFAT5, GRID_Gene_Symbol: NFAT5, GRID_Transcript_ENS_Community submitted: ENST00000432919, GRID_Transcript_RefSeq: NM_138714.3, GRID_Transcript_ENS_used_on_Production: ENST00000432919

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