Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: IL6ST

Green List (high evidence)

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 12:01 p.m. | Last Modified: 24 Feb 2025, 12:01 p.m.

Panel Version: 7.26

Comment on mode of inheritance: As reviewed previously by Zornitza Stark, there is sufficient evidence available for the association of monoallelic IL6ST variants to this panel. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 2 Jul 2024, 4:21 p.m. | Last Modified: 2 Jul 2024, 4:23 p.m.

Panel Version: 5.10

PMID:32207811 reported the identification of seven different truncating IL6ST variants (one of which was recurrent) in 12 patients from eight unrelated kindred with autosomal dominant Hyper-IgE syndrome (AD-HIES). Overexpression of variant proteins led to their accumulation at the cell surface and are loss of function and dominant-negative for cellular responses to IL-6, IL-11, LIF, and OSM. In addition, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #619752, #619750, #618523 and #619751).

Created: 2 Jul 2024, 4:19 p.m. | Last Modified: 2 Jul 2024, 4:19 p.m.

Panel Version: 5.8

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections, OMIM:619752; ?Immunodeficiency 94 with autoinflammation and dysmorphic facies, OMIM:619750; Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections, OMIM:618523; Stuve-Wiedemann syndrome 2, OMIM:619751

Publications

• 32207811

Mode of pathogenicity
Other

PMID: 33517393 - Materna-Kiryluk et al 2021 - describe a patient with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphic features. The patient was found using exome sequencing to have a de novo IL6ST Tyr186_Tyr190del variant, which was present as a mosaic. It was found in around 15–40% of cells depending on the tissue (blood, urine sediment, hair bulbs and buccal swab).

Created: 4 May 2021, 6:26 p.m. | Last Modified: 4 May 2021, 6:26 p.m.

Panel Version: 2.419

Publications

• 33517393

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

Created: 4 Mar 2022, 10:17 a.m. | Last Modified: 4 Mar 2022, 10:17 a.m.

Panel Version: 2.529

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 3:05 p.m. | Last Modified: 20 Oct 2020, 3:05 p.m.

Panel Version: 2.342

Comment on list classification: Based on expert review and the reporting of additional variants.

Created: 5 May 2020, 4:07 p.m. | Last Modified: 5 May 2020, 4:07 p.m.

Panel Version: 2.158

Comment on phenotypes: Eosinophilia;Eczema;Bacterial infections, boiles, eczema, pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, retention of primary teeth, craniosynostosis;Abnormal acute-phase responses;Recurrent infections;Elevated IgE;Combined immunodeficiencies with associated or syndromic features

Created: 5 May 2020, 4:03 p.m. | Last Modified: 5 May 2020, 4:03 p.m.

Panel Version: 2.157

Green List (high evidence)

Also known as gp130. Two families with bi-allelic missense variants and immunological phenotype described initially. More recently, five individuals from three families reported with a more complex Stuve-Wiedemann-like phenotype reported, including skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. These three families had bi-allelic LoF variants (nonsense and canonical splice site). Several mouse models support gene-disease association.
2020: 12 individuals from 8 unrelated families with seven different mono-allelic truncating variants, dominant negative effect proposed.

Created: 10 Apr 2020, 8:20 a.m. | Last Modified: 10 Apr 2020, 8:20 a.m.

Panel Version: 2.51

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response.; Hyper-IgE syndrome, autosomal dominant

Publications

• 32207811
• 28747427
• 30309848
• 12370259
• 16041381
• 31914175

I don't know

Added publication referenced by IUIS december 2019 update

Created: 28 Feb 2020, 8:49 p.m. | Last Modified: 28 Feb 2020, 8:49 p.m.

Panel Version: 2.36

Comment on list classification: New gene added for review

Created: 26 Feb 2020, 4:30 p.m. | Last Modified: 26 Feb 2020, 4:30 p.m.

Panel Version: 2.5

New gene suggested by expert reviewer- unable to do a full curational review (Green rating recommended) as we are waiting for new PanelApp features before this gene can be added to this GMS panel.

Created: 22 Jan 2020, 11:36 a.m. | Last Modified: 22 Jan 2020, 11:36 a.m.

Panel Version: 2.0

Publications

• 30309848
• 28747427

Green List (high evidence)

At least two unrelated cases with homozygous loss-of-function variants and compelling functional support.

Created: 18 Jan 2020, 7:44 a.m. | Last Modified: 18 Jan 2020, 7:44 a.m.

Panel Version: 2.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hyper-IgE syndrome

Publications

• 28747427
• 30309848