Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: NLRP1

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in this gene to this panel. Hence, this gene can be promoted to green rating in the next GMS review.

Created: 2 Nov 2023, 2:20 p.m. | Last Modified: 2 Nov 2023, 2:42 p.m.

Panel Version: 4.113

There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).

Created: 2 Nov 2023, 2:13 p.m. | Last Modified: 2 Nov 2023, 2:43 p.m.

Panel Version: 4.113

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autoinflammation with arthritis and dyskeratosis, OMIM:617388; ?Respiratory papillomatosis, juvenile recurrent, congenital, OMIM:618803; Palmoplantar carcinoma, multiple self-healing, OMIM:615225; {Vitiligo-associated multiple autoimmune disease susceptibility 1}, OMIM:606579

Publications

• 27662089
• 27965258
• 31484767
• 31873740

Mode of pathogenicity
Other

I don't know

PMID: 31873740 report another patient with disease due to this gene - het missense variant in a patient with inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, tooth abnormalities and, eczema. Positive family history suggested autosomal dominant inheritance with incomplete penetrance.

Created: 18 Oct 2023, 11:51 a.m. | Last Modified: 18 Oct 2023, 11:51 a.m.

Panel Version: 4.50

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autoinflammatory disease with corneal and mucosal dyskeratosis

Publications

• 31873740

Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.

Created: 14 Oct 2020, 12:14 p.m. | Last Modified: 14 Oct 2020, 12:14 p.m.

Panel Version: 2.213

The following PubMed IDs were added to entity NLRP1: 27965258. These publications have been associated with OMIM phenotype MIM#617388, which is listed for this entity, by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Publications

• 27965258

PMID:27662089: Zhong et al., 2016 report germline GOF variants in NLRP1 which cause two overlapping skin disorders (MSPC and FKLC), linking NLRP1 to skin inflammatory syndromes.

Created: 29 Apr 2020, 8:33 p.m. | Last Modified: 29 Apr 2020, 8:33 p.m.

Panel Version: 2.138

PMID:31484767: Drutman et al., 2019 report 2 siblings with syndromic JRRP and a homozygous GOF variant in NLRP1.

Created: 29 Apr 2020, 8:33 p.m. | Last Modified: 29 Apr 2020, 8:33 p.m.

Panel Version: 2.138

Green List (high evidence)

Multiple phenotypes resulting from abnormal inflammatory response associated with this gene, both mono-allelic and bi-allelic, some gain-of-function (including bi-allelic).
Bi-allelic disease: single family with dyskeratosis, autoimmunity and arthritis and another family with bi-allelic GoF and recurrent respiratory papillomatosis phenotype
Mono-allelic disease: mostly pertains to the association with multiple self-healing palmoplantar carcinomas (MSPC). One consanguineous family in which a sister and brother with clinical features of MSPC as well as multiple discrete and semiconfluent lichenoid papules on the arms, legs, and lower trunk were homozygous for an in-frame deletion in the NLRP1 gene, and parents had milder skin defects. The clinical diagnosis in this family was familial keratosis lichenoides chronica (Nekam disease).

Created: 11 Apr 2020, 4:44 a.m. | Last Modified: 11 Apr 2020, 4:44 a.m.

Panel Version: 2.51

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autoinflammation with arthritis and dyskeratosis, MIM# 617388; Palmoplantar carcinoma, multiple self-healing 615225; Recurrent respiratory papillomatosis

Publications

• 27965258
• 31484767
• 27662089

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

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

Original Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): NLRP1 .PanelApp HGNC gene symbol check: NLRP1 . IUIS Disease: NLRP1 deficiency . IUIS Inheritance: AR / AD GOF .T cells: Normal / Normal, .B cells: Normal / Normal, Immunoglobulin levels: Normal / Normal, Neutrophil count: Normal / Normal IUIS Other affected cells: leukocytes / Keratinocytes. IUIS Associated features: Dyskeratosis, autoimmunity and arthritis / Palmoplantar carcinoma, corneal scarring, IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Defects Affecting the Inflammasome

Created: 28 Feb 2020, 4:41 p.m. | Last Modified: 28 Feb 2020, 4:41 p.m.

Panel Version: 2.27

Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.

Created: 12 Nov 2019, 5:02 p.m. | Last Modified: 12 Nov 2019, 5:02 p.m.

Panel Version: 1.137

Autoinflammation - two cases, ?AD / AR – unclear

Created: 26 Sep 2019, 3:57 p.m. | Last Modified: 26 Sep 2019, 3:57 p.m.

Panel Version: 1.130

Comment on list classification: Upgraded from Red to Amber. This is a relevant phenotype but there is not enough evidence in the literature to date (only two reported cases) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.

Created: 17 Sep 2019, 5:14 p.m. | Last Modified: 17 Sep 2019, 5:22 p.m.

Panel Version: 1.101

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Comment on publications: PMID: 29850521- Psoriasis Vulgaris Risk

Created: 6 Jul 2018, 3:36 p.m.

Comment on publications: added publications suggested from external expert review

Created: 6 Jul 2018, 3:13 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): NLRP1 .PanelApp HGNC gene symbol check: NLRP1 . IUIS Disease: NLRP1 deficiency . IUIS Inheritance: AR .T cells: Normal, .B cells: N/A, .IUIS Other affected cells: leukocytes. IUIS Associated features: Dyskeratosis, autoimmunity and arthritis. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Defects Affecting the Inflammasome

Created: 6 Jul 2018, 12:30 p.m.

Publications

• 27662089
• 31484767

I don't know

Single report, 2 sibs with homozygous variant and one singleton with a heterozygous missense mutation

Created: 29 Jun 2018, 9:57 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autoinflammation with arthritis and dyskeratosis

Publications

• 27965258