Primary immunodeficiency or monogenic inflammatory bowel disease
Gene: FASLGThe mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.Created: 2 Feb 2023, 11:32 a.m. | Last Modified: 2 Feb 2023, 11:32 a.m.
Panel Version: 3.4
Comment on mode of inheritance: There are 3 cases with Autoimmune lymphoproliferative syndrome reported with homozygous variants in FASLG but also 2 reports of milder cases with heterozygous variants (not fully penetrant) so a change of mode of inheritance to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" should be considered following GMS review.Created: 19 Apr 2022, 3:25 p.m. | Last Modified: 19 Apr 2022, 3:25 p.m.
Panel Version: 2.546
Comment on publications: Removed publications with the following PMIDS as not specifically about patients with variants in FASLG: 26907631;16537120;8806292;22983577;16394653Created: 19 Apr 2022, 3:22 p.m. | Last Modified: 19 Apr 2022, 3:22 p.m.
Panel Version: 2.545
Checking the mode of inheritance for this gene because in OMIM it is associated with Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859 with an autosomal dominant inheritance pattern listed (page last updated in 2014). Note the FASLG gene has previously been known as TNFSF6 and FASL). The FAS gene has previously been know as TNFRSF6.
Patients with homozygous variants:
PMID: 16627752 - Del-Rey et al 2006 - describe a Spanish patient with an ALPS phenotype and with a homozygous missense variant in FASL (A247E). The healthy mother was heterozygous for the variant. DNA from the father was not available.
PMID: 22857792 - Magerus-Chatinet et al 2013 - patient with a a severe form of ALPS who was found to have a homozygous 1-bp deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation.
PMID:25451160 - Nabhani et al 2014 - 2 siblings from a consanguineous Libyan family who presented with a severe phenotype of autoimmune lymphoproliferative syndrome (ALPS) were found by Sanger sequencing of FASLG to have a homozygous 1 bp insertion predicted to result in a frameshift and a truncated protein (p.P69Afs*75). The healthy mother was heterozygous for the variant.
Patients with heterozygous variants:
PMID: 8787672 - Wu et al 1996 - in a 64 year old African American male patient with systemic lupus erythematosus with lymphadenopathy they identified a heterozygous 84bp deletion within exon 4 of FASLG that results in a in-frame deletion using single stranded conformational polymorphism (SSCP).. The found decreased FasL activity in PBMC , decreased activation-induced cell death, and increased T cell proliferation after activation.
PMID: 17605793 - Bi et al 2007 - report an ALPS Type 1b white male patient with a heterozygous A530G mutation in the FasL gene. This variant was also found in his father and paternal grandmother. The father had lymphadenopathy as an adolescent but has been healthy otherwise except for psoriatic arthritis. The grandmother is not reported to have symptoms of ALPS. They show that the variant results in a dominant-interfering FasL protein that binds to the wild-type FasL protein and prevented it from effectively inducing apoptosis.
Other publications linked to this gene by the Human Phenotype Ontology Immune Mediated Disorders Consortium refer more to the phenotype of ALPS and not to FASLG variants specifically (PubMed IDs: 26907631, 16537120, 8806292, 22983577, 16394653).Created: 19 Apr 2022, 1:38 p.m. | Last Modified: 19 Apr 2022, 1:38 p.m.
Panel Version: 2.542
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, 12:55 p.m. | Last Modified: 14 Oct 2020, 12:55 p.m.
Panel Version: 2.250
The following PubMed IDs were added to entity FASLG: 25451160;7511063;16537120;22857792;8806292;22983577;16394653;26907631. These publications have been associated with OMIM phenotype MIM#601859, 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
agree with green geneCreated: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
YES- this is covered on our targeted exomeCreated: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.
Panel Version: 1.94
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
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): FASLG .PanelApp HGNC gene symbol check: FASLG . IUIS Disease: ALPS-FASLG . IUIS Inheritance: AR .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated. 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 mode of inheritance: Corrected MOI from external reviewCreated: 20 Jun 2018, 2:37 p.m.
Germline mutations in the FAS (10q24.1), FASLG (1q23), or CASP10 (2q33-q34) genes are known to be associated with ALPSCreated: 18 Jun 2018, 2:23 p.m.
Comment on list classification: changed from Amber to GreenCreated: 18 Jun 2018, 2:22 p.m.
Comment on publications: Added publications to support phenotype.Created: 18 Jun 2018, 2:16 p.m.
Comment on phenotypes: added OMIM MIMidCreated: 18 Jun 2018, 2:09 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: FASL (CD178) (ALPS IB), PanelApp HGNC gene symbol check: FASLG, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Diseases of immune dysregulation / Autoimmune lymphoproliferative syndrome (ALPS) / Autoimmune lymphoproliferative syndrome (ALPS)Created: 17 Apr 2018, 12:29 p.m.
Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: FASLG, GRID_Gene_Symbol: FASLG, GRID_Transcript_ENS_Community submitted: ENST00000367721, GRID_Transcript_RefSeq: NM_000639.1, GRID_Transcript_ENS_used_on_Production: ENST00000367721Created: 17 Apr 2018, 12:12 p.m.
Tag Q2_22_MOI was removed from gene: FASLG.
Mode of inheritance for gene FASLG was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mode of inheritance for gene: FASLG was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Tag Q2_22_MOI tag was added to gene: FASLG.
Publications for gene: FASLG were set to 8806292; 16537120; 16394653; 8787672; 20301287; 17605793; 26907631; 27848183; 25451160; 22857792; 7511063; 22983577
Phenotypes for gene: FASLG were changed from Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; SLE to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; systemic lupus erythematosus (SLE)
Phenotypes for gene: FASLG were changed from Autoimmune lymphoproliferative syndrome, type IB, 601859; Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG); Autoimmune lymphoproliferative syndrome (ALPS); Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated; Diseases of Immune Dysregulation to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; SLE
Gene: faslg has been classified as Green List (High Evidence).
Source Other was added to FASLG. Publications for gene FASLG were updated from 17605793; 20301287; 8787672; 17605793; 27848183 to 8806292; 16537120; 16394653; 8787672; 20301287; 17605793; 26907631; 27848183; 25451160; 22857792; 7511063; 22983577 Rating Changed from Green List (high evidence) to Red List (low evidence)
Source NHS GMS was added to FASLG.
Source North West GLH was added to FASLG.
Source London North GLH was added to FASLG.
2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.
Phenotypes for gene FASLG were set to Autoimmune lymphoproliferative syndrome, type IB, 601859, Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG), Autoimmune lymphoproliferative syndrome (ALPS), Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated, Diseases of Immune Dysregulation
IUIS Classification February 2018 was added to FASLG. Panel: Primary immunodeficiency disorders
Victorian Clinical Genetics Services was added to FASLG. Panel: Primary immunodeficiency disorders
Gene: faslg has been classified as Green List (High Evidence).
Mode of inheritance for gene: FASLG was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Gene: faslg has been classified as Green List (High Evidence).
Publications for gene: FASLG were set to 17605793; 20301287; 8787672; 17605793; 27848183
Phenotypes for gene: FASLG were set to Autoimmune lymphoproliferative syndrome, type IB, 601859; Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG); Autoimmune lymphoproliferative syndrome (ALPS)
Expert Review Amber was added to FASLG. Panel: Primary immunodeficiency disorders
ESID Registry 20171117 was added to FASLG. Panel: Primary immunodeficiency disorders Phenotypes for gene FASLG were set to Autoimmune lymphoproliferative syndrome, type IB, Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG), Autoimmune lymphoproliferative syndrome (ALPS)
Phenotypes for gene FASLG were set to Autoimmune lymphoproliferative syndrome, type IB, Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG)
GRID V2.0 was added to FASLG. Panel: Primary immunodeficiency disorders Phenotypes for gene FASLG were set to Autoimmune lymphoproliferative syndrome, type IB, Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG)
FASLG Source: GOSH PID 20171150 was removed from gene: FASLG
GOSH PID v.8.0 was added to FASLG. Panel: Primary immunodeficiency disorders
FASLG was added to Primary immunodeficiency disorders panel. Sources: GOSH PID 20171150
FASLG was created by Louise Daugherty