Hereditary systemic amyloidosis

Gene: NLRP3

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber.

This is the comment from the national provider at North Thames GLH: This gene is well known cause of Cryopyrin-associated periodic syndrome (CAPS), a rare hereditary autoinflammatory disorder and is included in R413 autoinflammatory panel. It shouldn't be added to this panel because patients with Muckle-Wells syndrome who are referred with a query autoinflammatory disorder will undergo screening for the R413 autoinflammatory panel and not R204 amyloid panel.

Created: 4 Dec 2024, 10:39 p.m. | Last Modified: 4 Dec 2024, 10:43 p.m.

Panel Version: 1.24

Comment on list classification: Changed rating 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.

Created: 19 Oct 2020, 4:20 p.m. | Last Modified: 19 Oct 2020, 4:20 p.m.

Panel Version: 1.8

Comment on list classification: Updated rating from Grey to Green. NLRP3 was added to panel and rated Green by Zornitza Stark. Not yet in G2P but sufficient cases to support gene:disease association for NLRP3:Muckle-Wells syndrome, and approx 25-30% of MWS cases have an AA amyloidosis phenotype. Cases of NRLP3 variants in amyloidosis patients reported in PMIDs 30431487, 11992256. In summary: sufficient evidence to support association with MWS, and 25-30% of MWS patients have amyloidosis.

Created: 25 Mar 2020, 10:09 p.m. | Last Modified: 25 Mar 2020, 10:09 p.m.

Panel Version: 1.7

PMID:11992256 (Dode et al., 2002) identify NLRP3 (CIAS1) variants in 9 unrelated families with MWS. AA amyloidosis is recorded amongst the phenotypes in family 1 (R260W variant).

Created: 25 Mar 2020, 9:57 p.m. | Last Modified: 25 Mar 2020, 9:57 p.m.

Panel Version: 1.6

PMID:30431487 (Pandiarajan et al., 2018) report a 10-yr old child with nephrotic syndrome. The patient had a NLRP3 variant (c.1055C>T, p.Ala352Val) and features including AA amyloidosis.

Created: 25 Mar 2020, 9:47 p.m. | Last Modified: 25 Mar 2020, 9:47 p.m.

Panel Version: 1.6

PMID:31057541 (Fingerhutová et al. 2019) report 1 family (11 individuals) with MWS and a p.Ala441Val variant in NLRP3. 2 patients aged over 50 years suffered with hearing loss and AA amyloidosis.

Created: 25 Mar 2020, 9:47 p.m. | Last Modified: 25 Mar 2020, 9:47 p.m.

Panel Version: 1.6

PMID:27435956 (Villalba et al., 2016) report a 5-year old MWS patient with T348M variant in NLRP3. They report that amyloidosis and hearing loss is seen in ~25% of patients.

Created: 25 Mar 2020, 9:47 p.m. | Last Modified: 25 Mar 2020, 9:47 p.m.

Panel Version: 1.6

PMID:28229991 (Hu et al., 2017) report a patient with periodic fever, arthralgia and skin lesions and an A92T variant in NLRP3 (p.D31V).

Created: 25 Mar 2020, 9:47 p.m. | Last Modified: 25 Mar 2020, 9:47 p.m.

Panel Version: 1.6

PMID:11687797 (Hoffman et al., 2001) studied 1 family (family 4, 2 individuals) with MWS and a de novo C1055T (p.A352V) variant in NLRP3 (aka CIAS1). Arthrogryposis isn't specifically mentioned amongst phenotypes.

Created: 25 Mar 2020, 9:47 p.m. | Last Modified: 25 Mar 2020, 9:47 p.m.

Panel Version: 1.6

Green List (high evidence)

Renal amyloidosis described in this disorder.
Sources: Expert list

Created: 30 Jan 2020, 4:27 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Muckle-Wells syndrome

Publications

• 11687797
• 28229991
• 27435956
• 31057541