Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: POLE

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, 3:19 p.m. | Last Modified: 20 Oct 2020, 3:19 p.m.

Panel Version: 2.347

Comment on list classification: Updated rating from Amber to Green following review by Zornitza Stark: >3 cases from 3 separate papers of individuals with biallelic POLE variants and a phenotype that includes immunodeficiency.

Created: 29 Apr 2020, 4:58 p.m. | Last Modified: 29 Apr 2020, 4:58 p.m.

Panel Version: 2.134

PMID:23230001: 1 large consanguineous family with FILS syndrome (all but 2 patients suffered from immunodeficiency) and homozygous single bp substitution in POLE1.

Created: 29 Apr 2020, 4:57 p.m. | Last Modified: 29 Apr 2020, 7:58 p.m.

Panel Version: 2.134

PMID:25948378 (Thiffault et al., 2015) report a girl with immune deficiency amongst her phenotypes. She was homozygous for a splice variant in POLE1 (c.4444 + 3A > G).

Created: 29 Apr 2020, 4:56 p.m. | Last Modified: 29 Apr 2020, 4:56 p.m.

Panel Version: 2.133

PMID:30503519 (Logan et al., 2018) report biallelic variants in POLE in 15 indivs from 12 families (mix of countries). All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. Phenotypically, affected individuals all had IUGR and severe growth failure of prenatal onset. Immunodeficiency in 9 families (either increased susceptibility to infections or documented lymphopenia/ hypogammaglobinemia).

Created: 29 Apr 2020, 4:33 p.m. | Last Modified: 29 Apr 2020, 4:33 p.m.

Panel Version: 2.133

Green List (high evidence)

Both the FILS and IMAGE-I phenotypes have immunodeficiency as a feature. Note recurrent intronic variant, c.1686+32C-G (intron 15) in IMAGE-I, found in combination with multiple other variants.

Created: 11 Apr 2020, 5:08 a.m. | Last Modified: 11 Apr 2020, 5:08 a.m.

Panel Version: 2.51

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
FILS syndrome, MIM# 615139; IMAGE-I syndrome, MIM# 618336

Publications

• 30503519
• 23230001
• 25948378

I don't know

Only one family described

Created: 29 Jun 2018, 3:05 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Associated with phenotypes in OMIM and as a probable Gen2Phen gene for {Colorectal cancer, susceptibility to, 12} 615083. At least 1 variant identified in affected members of a single family with FILS syndrome 615139. Supportive in vitro studies also presented (PMID 23230001)

Created: 9 May 2018, 12:57 p.m.

Comment on phenotypes: Autosomal dominant variants also associated with {Colorectal cancer, susceptibility to, 12} 615083.

Created: 9 May 2018, 12:41 p.m.

I don't know

Keep Amber until more info on gene and disease association regarding immunological phenotype. Only one family reported but with supportive in vitro studies . Request evidences from GRID and Victorian Clinical Genetics Services

Created: 4 Jul 2018, 5:55 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): POLE .PanelApp HGNC gene symbol check: POLE . IUIS Disease: POLE1 (Polymerase _ subunit 1) deficiency (FILS syndrome) . IUIS Inheritance: AR .T cells: Low CD4 cells, .B cells: Low memory B cells, .IUIS Other affected cells: N/A. IUIS Associated features: Recurrent respiratory infections, meningitis, facial dysmorphism, livido, short stature . IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: DNA Repair Defects other than those listed in Table 1

Created: 2 Jul 2018, 10:35 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: POLE1, PanelApp HGNC gene symbol check: POLE, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Other well defined PIDs / FILS syndrome / Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS syndrome)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: POLE, GRID_Gene_Symbol: POLE, GRID_Transcript_ENS_Community submitted: ENST00000320574, GRID_Transcript_RefSeq: NM_006231.3, GRID_Transcript_ENS_used_on_Production: ENST00000320574

Created: 17 Apr 2018, 12:12 p.m.