Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: NFATC2

I don't know

Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence.

The 'watchlist' tag has been added as there is an additional patient reported in a conference abstract with relevant phenotype. Hence, this gene should be reviewed and updated when additional published evidence become available.

Created: 13 Aug 2026, 8:50 a.m. | Last Modified: 14 Aug 2026, 10:57 a.m.

Panel Version: 9.102

PMID:35789258 (2022) reported the first patient with complete NFAT1 (NFATC2) deficiency identified with a homozygous frameshift variant (c.2023_2026delTACC; p.Tyr675Thrfs*18). The patient presented with presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma, and immune profile showed accumulation of naïve B cells with oncogenic signatures (MYC, JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, aberrant CD8+ T cells.

PMID:38427060 (2024) reported a 12-year-old female patient identified with a homozygous 6bp in-frame deletion (c.340_345delGAGATC; p.Glu114_Ile115del) and presenting with EBV-associated lymphoproliferation without skeletal involvement. This patient had recurrent chest infections, chronic wet cough, failure to thrive, generalised lymphadenopathy and severe hypogammaglobulinemia. The father and the healthy brother of the patient were heterozygous for the variant.

As reviewed by Boaz Palterer, Bustamante-Ogando et al (2025) reported in a conference abstract (NOT a peer-reviewed manuscript) of a 12-year-old female patient with a severe, early-onset immunodeficiency characterised by recurrent sinopulmonary infections, bloody diarrhoea, chronic lung disease, and profound failure to thrive. Immunological analysis revealed anaemia and thrombocytosis, as well as pan-hypogammaglobulinemia, with reduced CD4+ and CD8+ T cells. Whole exome sequencing identified two novel, ultra-rare, highly conserved compound heterozygous missense variants in NFATC2 (p.Gly408Arg & p.Arg646Gln).

This gene has been provisionally associated with MIM #620232 in OMIM (last accessed 11 August 2024).

Created: 13 Aug 2026, 8:49 a.m. | Last Modified: 13 Aug 2026, 8:49 a.m.

Panel Version: 9.92

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537

Publications

• 35789258
• 38427060

Red List (low evidence)

NFATC2 (also known as NFAT1) encodes the nuclear factor of activated T cells 2, a critical calcium/calcineurin-dependent transcription factor essential for T cell activation, immune homeostasis, and cell fate regulation.

Sharma et al. identified 1 patient from 1 family carrying a homozygous pathogenic NFATC2 frameshift variant (p.Tyr675Thrfs*18) presenting with progressive joint contractures, osteochondromas, and B cell malignancy.

Bustamante-Ogando et al. identified 1 patient from 1 family carrying compound heterozygous NFATC2 missense variants (p.Gly408Arg/p.Arg646Gln) presenting with severe early-onset immunodeficiency, recurrent sinopulmonary infections, bloody diarrhea, chronic lung disease, and pan-hypogammaglobulinemia.
( https://doi.org/10.70962/LASID2025abstract.69 )
Sources: Literature

Created: 17 Jun 2026, 3:58 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
progressive joint contractures; osteochondromas; B cell malignancy; diarrhea; chronic lung disease; hypogammaglobulinemia

Publications

• 35789258