Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: FADD

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, 12:46 p.m. | Last Modified: 14 Oct 2020, 12:46 p.m.

Panel Version: 2.248

The following PubMed IDs were added to gene FADD (OMIM gene MIM#602457): 18070632;25794656;21109225. These publications have been associated with the gene 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

• 18070632
• 25794656
• 21109225

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)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
functional hyposplenism; invasive pneumococcal disease; para-infectious encephalopathy and hepatopathy; cardiovascular malformations

Publications

• 21109225
• 25794656

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): FADD .PanelApp HGNC gene symbol check: FADD . IUIS Disease: FADD deficiency . IUIS Inheritance: AR .T cells: Normal numbers, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Autoimmune Lymphoproliferative Syndrome (ALPS, Canale Smith syndrome)

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

Comment on list classification: Changed Amber to Green from external review comment and further publications to support gene-disease association

Created: 20 Jun 2018, 10:22 p.m.

Comment on phenotypes: Added phenotypes suggested from external expert review.

Created: 20 Jun 2018, 10:20 p.m.

Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green

Created: 20 Jun 2018, 10:19 p.m.

Keep Amber until more info on gene and disease association, refer to external expert review

Created: 18 Jun 2018, 1:30 p.m.

Characterized by severe bacterial and viral infections, congenital heart defects and recurrent episodes of fever, liver
dysfunction, and seizures.

Created: 18 Jun 2018, 1:22 p.m.

Comment on publications: FADD-related immunodeficiency is a rare genetic immunological disease reported in a single consanguineous Pakistani family with several affected members presenting with severe bacterial and viral infections, recurrent hepatopathy (portal inflammation, fibrosis), and recurrent, stereotypical febrile episodes, sometimes lasting several days, with encephalopathy and difficult-to-control seizure. Bolze et al. (2010) PMID: 21109225 reported 2 sisters and their cousin from a large consanguineous Pakistani pedigree with recurrent infections associated with encephalopathy, hepatic dysfunction, and cardiovascular malformations caused by a 315T-G transversion in exon 2. The mutation segregated with disease in the family and was not found in 282 Pakistani controls. Bolze et al. (2010) concluded that the C105W mutation strongly decreases steady-state protein levels and impairs the interaction of the residual FADD protein with FAS. Analysis of FAS-induced apoptosis in patients' cells confirmed that the C105W mutant impairs apoptotic function both in vitro and in vivo.

Created: 18 Jun 2018, 1:10 p.m.

Comment on mode of inheritance: added MOI

Created: 18 Jun 2018, 1:05 p.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: FADD, PanelApp HGNC gene symbol check: FADD, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Autoimmune lymphoproliferative syndrome (ALPS) / ALPS-like disease

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

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: FADD, GRID_Gene_Symbol: FADD, GRID_Transcript_ENS_Community submitted: ENST00000301838, GRID_Transcript_RefSeq: NM_003824.3, GRID_Transcript_ENS_used_on_Production: ENST00000301838

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