Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: NFATC1

I don't know

Comment on list classification: There is only one case and functional evidence available in support of the association of NFATC1 with immunodeficiency. Hence, this gene should be rated amber with the current evidence.

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

Panel Version: 9.97

PMID:37249233 (2023) reported three patients from a multigenerational pedigree presenting with early-onset sinopulmonary infections leading to bronchiectasis, recurrent viral/bacterial skin infections (in P2/P3), surgically corrected scoliosis (in P1/P2), and hypogammaglobulinemia with impaired vaccine responses. Immunophenotyping showed a lower CD4+:CD8+ T-cell ratio and reduced recent thymic emigrants in all three patients, along with defective lymphocyte proliferation responses to PHA and CD3/CD28 stimulation. These patients were identified with compound heterozygous missense variants in NFATC1 gene (c.1361C>T/ p.Ser454Leu and c.2233G>A, p.Val745Met).

Functional studies showed that the NFATC1 variants reduced protein stability and DNA/protein binding, impaired T- and B-cell activation and proliferation, and disrupted glycolytic metabolism in T cells—defects that were rescued by genetic reconstitution and partially corrected pharmacologically with metformin and rosiglitazone.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen, although it is associated with congenital heart disease (MONDO:0005453) with ‘limited’ rating in ClinGen (last accessed 11 August 2026).

Created: 13 Aug 2026, 8:56 a.m. | Last Modified: 13 Aug 2026, 8:56 a.m.

Panel Version: 9.95

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
inborn error of immunity, MONDO:0003778

Publications

• 37249233

Red List (low evidence)

NFATC1 encodes the nuclear factor of activated T cells 1, a key transcription factor critical for T and B cell activation, proliferation, and adaptive immune homeostasis.

Kostel Bal et al. identified 3 patients from 1 family carrying biallelic pathogenic NFATC1 missense variants presenting with recurrent infections, hypogammaglobulinemia, and decreased antibody responses due to these profound metabolic and proliferative defects.
Sources: Literature

Created: 17 Jun 2026, 4 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
recurrent infections; hypogammaglobulinemia; decreased antibody responses

Publications

• 37249233