Autoinflammatory disorders

Gene: ALPK1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 10 Dec 2025, 2:17 p.m. | Last Modified: 10 Dec 2025, 2:17 p.m.

Panel Version: 2.34

Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for the association of ALPK1 with an auto-inflammatory condition, ROSAH. Hence, this gene can be promoted to green rating on this panel in the next GMS update.

Created: 13 Jun 2025, 11:11 a.m. | Last Modified: 13 Jun 2025, 11:11 a.m.

Panel Version: 2.10

This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

Gain-of-function missense variants in ALPK1 were reported to cause ROSAH in PMID:35868845.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/) It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.

Created: 13 Jun 2025, 11:02 a.m. | Last Modified: 13 Jun 2025, 11:07 a.m.

Panel Version: 2.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
ROSAH syndrome, OMIM:614979

Publications

• 30967659
• 35868845
• 36332842
• 38251500
• 40069099

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)

Sources: Expert list

Created: 4 Jun 2025, 3:40 p.m. | Last Modified: 4 Jun 2025, 4:29 p.m.

Panel Version: 2.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and migraine Headache syndrome (ROSAH)

Publications

• PMID: 30967659
• PMID: 36332842
• PMID: 38251500
• PMID: 40069099
• PMID: 35868845