Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: STAT4

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 3:34 p.m. | Last Modified: 26 Sep 2024, 3:34 p.m.

Panel Version: 6.10

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (three unrelated cases and functional studies) for the association of this gene with disabling pansclerotic morphea of childhood (MIM #620443) and hence this gene can be promoted to green rating in the next GMS review.

Created: 14 Feb 2024, 1:44 p.m. | Last Modified: 14 Feb 2024, 1:47 p.m.

Panel Version: 4.171

Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that STAT4 variants caused a gain-of-function effect.

Created: 14 Feb 2024, 1:41 p.m. | Last Modified: 14 Feb 2024, 1:42 p.m.

Panel Version: 4.170

Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #612253 & #620443), but not in Gene2Phenotype.

Created: 14 Feb 2024, 1:37 p.m. | Last Modified: 14 Feb 2024, 1:37 p.m.

Panel Version: 4.167

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Disabling pansclerotic morphea of childhood, OMIM:620443; {Systemic lupus erythematosus, susceptibility to, 11}, OMIM:612253

Publications

• 37256972

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

PMID: 37256972 (2023) identified 4 patients from 3 unrelated families with disabling pansclerotic morphea of childhood, Heterozygous missense mutations in STAT4 identified in all:
A635V in 2 brothers inherited from their mildly affected father
A650D in a Greek man and his moderately affected mother
H623Y in a 17-year-old boy which was de novo
"Functional analysis demonstrated that the mutations caused a gain-of-function effect, and inhibition of JAK (JAK1; 147795)-STAT signaling with ruxolitinib resulted in improvement in the hyperinflammatory fibroblast phenotype in vitro as well as attenuation of inflammatory markers and clinical symptoms in the 2 treated patients (the affected brothers in family 1)."

Created: 7 Feb 2024, 9:39 a.m. | Last Modified: 7 Feb 2024, 9:39 a.m.

Panel Version: 4.163

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Disabling pansclerotic morphea of childhood

Publications

• PMID: 37256972

Comment on list classification: Only one kindred reported with a heterozygous variant in STAT4 associated with susceptibility to paracoccidioidomycosis. Additional cases needed to validate pathogenicity and therefore keeping rating Red.

Created: 7 Oct 2020, 1:16 p.m. | Last Modified: 7 Oct 2020, 1:16 p.m.

Panel Version: 2.200

- PMID: 29029192 (2017) - A heterozygous missense variant (c.1952 A>T, p.E651V) in STAT4 was identified in a female and her father, with a history of paracoccidioidomycosis. In vitro analysis using patient lymphocytes showed reduced STAT4 phosphorylation, nuclear translocation, and impaired IL-12–induced IFN-γ immunity.

Created: 7 Oct 2020, 1:13 p.m. | Last Modified: 7 Oct 2020, 1:13 p.m.

Panel Version: 2.199

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 29029192

Red List (low evidence)

Mode of inheritance
Unknown

Phenotypes
Paracoccidioidomycosis; Impaired IFN-γ Immunity

Publications

• 29029192

Red List (low evidence)

Potential risk allele for SLE. New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID so was rated as Red by the group.

Created: 27 Sep 2019, 2:54 p.m. | Last Modified: 27 Sep 2019, 2:54 p.m.

Panel Version: 1.132