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STAT1 – Immunodeficiency 31B

Signal transducer and activator of transcription 1 (STAT1) deficiency underlies autosomal recessive Immunodeficiency 31B, characterized by early-onset disseminated mycobacterial and severe viral infections with impaired IFN-γ and IFN-α signaling (PMID:21772053).

Biallelic STAT1 loss-of-function variants include a homozygous splice site mutation causing exon 3 skipping and truncated protein (PMID:21772053), and a homozygous missense allele c.2086C>T (p.Pro696Ser) leading to partial STAT1 deficiency (PMID:19436109).

Additional patients presented AR STAT1 deficiency manifesting as Mycobacterium szulgai osteomyelitis in adolescence (PMID:24569307) and infantile disseminated BCG-induced osteomyelitis (PMID:36349275), expanding the phenotypic spectrum of immunodeficiency 31B.

Functional assays in patient-derived cells demonstrate marked reduction of STAT1 phosphorylation upon IFN-γ and IFN-α stimulation, complete loss of DNA-binding activity by EMSA, and impaired NK cell cytotoxicity (PMID:21772053).

The pathogenic mechanism involves autosomal recessive loss of STAT1 function leading to failure of JAK–STAT signaling in innate and adaptive immune cells.

Early genetic testing for STAT1 LOF variants enables definitive diagnosis of immunodeficiency 31B, guiding consideration of targeted therapies such as IFN-γ supplementation or hematopoietic stem cell transplantation.

References

  • Blood • 2011 • Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation PMID:21772053
  • The Pediatric infectious disease journal • 2013 • Mycobacterium szulgai chronic multifocal osteomyelitis in an adolescent with inherited STAT1 deficiency. PMID:24569307
  • Open forum infectious diseases • 2022 • Multiple Lytic Bone Lesions Mimicking Langerhans Cell Histiocytosis: A Case of Infantile Mendelian Susceptibility to Mycobacterial Disease due to STAT1 Deficiency. PMID:36349275
  • The Journal of clinical investigation • 2009 • A partial form of recessive STAT1 deficiency in humans. PMID:19436109

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

Four probands with biallelic STAT1 LOF variants demonstrating complete or partial immunodeficiency (PMID:21772053, PMID:24569307, PMID:36349275, PMID:19436109)

Genetic Evidence

Moderate

Four probands with autosomal recessive inheritance, variant spectrum includes splice and missense LOF alleles; reached moderate case count cap.

Functional Evidence

Moderate

Patient cells show impaired STAT1 phosphorylation, absent DNA binding by EMSA, and NK cell dysfunction supporting LOF mechanism.