Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: UNC13D

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green 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, 4:46 p.m. | Last Modified: 14 Oct 2020, 4:46 p.m.

Panel Version: 2.331

The following PubMed IDs were added to entity UNC13D: 27914778;14622600;17993578;29312353. These publications have been associated with OMIM phenotype MIM#608898, which is listed for this entity, by the immunedysregulation 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

• 27914778
• 14622600
• 17993578
• 29312353

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

Green List (high evidence)

Green List (high evidence)

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

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): UNC13D .PanelApp HGNC gene symbol check: UNC13D . IUIS Disease: UNC13D / Munc13-4 deficiency (FHL3) . IUIS Inheritance: AR , .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Fever, HSM, HLH, cytopenias, . IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Familial Hemophagocytic Lymphohistiocytosis (FHL syndromes)

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

Comment on list classification: Changed status from Amber to Green, there are more than 3 unrelated cases to support the phenotype Familial hemophagocytic lymphohistiocytosis-3 (FHL3) caused by homozygous or compound heterozygous mutation in the gene encoding perforin UNC13D

Created: 30 Apr 2018, 11:36 a.m.

from GeneReview PMID:20301617: Approx 20%-30% 3, 5 worldwide of FHL are FHL3 (Hemophagocytic lymphohistiocytosis, familial, 3) PMID:15632205, PMID:15703195.

Created: 30 Apr 2018, 11:33 a.m.

Comment on publications: added publication PMID: 17993578 to support age-specific-variation tag eg: this gene is not specific to early onset

Created: 30 Apr 2018, 11:30 a.m.

Added age-specific-variation tag

Created: 30 Apr 2018, 11:28 a.m.

from OMIM: Feldmann et al. (2003) PMID: 14622600 Identified 6 different mutations in the UNC13D gene in 10 patients from 7 unrelated families with Hemophagocytic lymphohistiocytosis-3 (FHL3). In a Turkish patient from a consanguineous family with primary hemophagocytic lymphohistiocytosis, Zur Stadt et al. (2006) PMID:16278825 identified homozygosity for a missense mutation in the UNC13D gene.
Rudd et al. (2008) PMID: 17993578 reported 9 patients from 6 families with genetically confirmed FHL3. There was considerable variation in age at diagnosis, ranging from birth to 14 years, and 3 of the 9 mutation-positive patients developed central nervous system symptoms. Natural killer cell activity was impaired in all 4 patients studied. Defective cytotoxic lymphocyte degranulation was evident in the 2 patients investigated, and was more pronounced in the patient with onset during infancy than in the patient with adolescent onset.

Created: 30 Apr 2018, 11:26 a.m.

Comment on publications: Added publications to support role of UNC13D variants in Hemophagocytic lymphohistiocytosis, familial, 3

Created: 30 Apr 2018, 11:22 a.m.

Comment on phenotypes: added OMIM MIMid and synonyms

Created: 30 Apr 2018, 11:17 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: 19 Apr 2018, 10:55 a.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: UNC13D, PanelApp HGNC gene symbol check: UNC13D, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Hemophagocytic Lymphohistiocytosis (HLH) / Familial hemophagocytic lymphohistiocytosis syndromes (FHLH)

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: UNC13D, GRID_Gene_Symbol: UNC13D, GRID_Transcript_ENS_Community submitted: ENST00000207549, GRID_Transcript_RefSeq: NM_199242.2, GRID_Transcript_ENS_used_on_Production: ENST00000207549

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