Disorders of immune dysregulation

Gene: STAT3

Green List (high evidence)

Well-established disease-gene association for hyper-IgE syndrome; identified heterozygous STAT3 variants in over 50 familial and sporadic cases; dominant-negative loss of function; multiple mouse models Hyper IgE individuals presented with the triad of staphylococcal abscesses, pneumonia with pneumatocele formation, and extremely elevated IgE.

15 unrelated families with Autoimmune disease, multisystem, infantile-onset, 1; 13 STAT3 variants identified (5 were de novo); gain of function; multiple mouse models Autoimmune disease, multisystem, infantile-onset, 1 individuals exhibited various clinical features, with most presenting with lymphadenopathy, autoimmune cytopaenias, multiorgan autoimmunity, infections, and short stature. STAT3 monoallelic variants were missense and in-frame deletions in both diseases.

(Hyper IgE- Loss of Function AND Autoimmune disease- Gain of function)

Created: 12 Aug 2021, 8:28 a.m. | Last Modified: 12 Aug 2021, 8:28 a.m.

Panel Version: 0.8776

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hyper-IgE recurrent infection syndrome MIM# 147060; Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952

Publications

• 17881745
• 14566054
• 25349174
• 25038750
• 25359994

Green List (high evidence)

18 individuals from 15 unrelated families; Multiple mouse models

All 13 heterozygous variants reported have been missense or in-frame deletions that result in a gain of function; 5 of these de novo

Individuals exhibited various clinical features, with most presenting with lymphadenopathy, autoimmune cytopaenias, multiorgan autoimmunity, infections, and short stature.

Created: 12 Aug 2021, 6:28 a.m. | Last Modified: 12 Aug 2021, 6:28 a.m.

Panel Version: 0.92

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Autoimmune disease, multisystem, infantile-onset, 1 MIM# 615952; Lymphoproliferation; solid organ autoimmunity; recurrent infections; short stature; eczema; delayed puberty; dental abnormalities; autoimmune interstitial lung disease; juvenile-onset arthritis; primary hypothyroidism

Publications

• 25349174
• 25038750
• 25359994
• 16783372

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