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Primary immunodeficiency or monogenic inflammatory bowel disease v6.2 CASP10 Sarah Leigh edited their review of gene: CASP10: Added comment: PMID: 38704374, aimed to assess the impact of CASP10 variants on autoimmune lymphoproliferative syndrome (ALPS) pathogenesis, by assessing the effect of CASP10 variants within the Imagine Institute's genetic platform (INSERM UMR 1163, Paris, France). Using this large dataset, the authors were able to confirm that the missense variants p.V410I and p.Y446C, are present in the general population at a high frequency. Furthermore, these variants do not affect the CASP10 catalytic domain and no difference was observed in CASP10 protein expression or FAS-mediated apoptosis between healthy controls and subjects bearing these variants in both homozygous and heterozygous states. Two patient had the CASP10 variant p.C401LfsX15, which is lies within QACQG catalytic site in the CASP10 catalytic domain. The patient S2 was homozygous for this variant, resulting in a lack of Caspase-10 RNA and protein. However, the authors report that "FAS-mediated apoptosis was surprisingly comparable to healthy controls in each of the tested cell lines suspected to have a role in ALPS". In patient S1, who was heterozygous p.C401LfsX15, the authors report that although the levels of CASP10 protein expression was reduced, there was normal FAS-mediated apoptosis compared to healthy controls. From these results, the authors conclude that it appears that "Caspase-10 is dispensable for FAS-mediated apoptosis: an undetectable CASP10 protein expression has no impact on lymphocyte apoptosis and on individuals’ clinical and laboratory phenotype". Although they do comment, that post-translational or epigenetic mechanisms may play a role, as yet unidentified.; Changed rating: AMBER; Changed publications to: 38704374
Primary immunodeficiency or monogenic inflammatory bowel disease v3.4 FASLG Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: FASLG.
Primary immunodeficiency or monogenic inflammatory bowel disease v3.4 FASLG Achchuthan Shanmugasundram commented on gene: FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease v3.3 FASLG Achchuthan Shanmugasundram 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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.555 SLC37A4 Arina Puzriakova Phenotypes for gene: SLC37A4 were changed from Glycogen storage disease Ic; Glycogen storage disease Ib, 232220; Glycogen storage disease Ib; Glycogen storage disease type 1b (GS1b); Glycogen storage disease with or without neutropenia; Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly; Congenital defects of phagocyte number or function to Glycogen storage disease Ib, OMIM:232220; Glycogen storage disease Ic, OMIM:232240; Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly; Congenital defects of phagocyte number or function
Primary immunodeficiency or monogenic inflammatory bowel disease v2.546 FASLG Eleanor Williams Added comment: 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.546 FASLG Eleanor Williams Mode of inheritance for gene: FASLG was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.545 FASLG Eleanor Williams Tag Q2_22_MOI tag was added to gene: FASLG.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.545 FASLG Eleanor Williams Added comment: Comment on publications: Removed publications with the following PMIDS as not specifically about patients with variants in FASLG: 26907631;16537120;8806292;22983577;16394653
Primary immunodeficiency or monogenic inflammatory bowel disease v2.545 FASLG Eleanor Williams Publications for gene: FASLG were set to 8806292; 16537120; 16394653; 8787672; 20301287; 17605793; 26907631; 27848183; 25451160; 22857792; 7511063; 22983577
Primary immunodeficiency or monogenic inflammatory bowel disease v2.544 FASLG Eleanor Williams 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)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.543 FASLG Eleanor Williams 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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.542 FASLG Eleanor Williams commented on gene: FASLG: 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).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.250 FASLG Eleanor Williams Classified gene: FASLG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.250 FASLG Eleanor Williams Gene: faslg has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.249 FAS Eleanor Williams Classified gene: FAS as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.249 FAS Eleanor Williams Added comment: 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.249 FAS Eleanor Williams Gene: fas has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FASLG Eleanor Williams 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)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 FAS Eleanor Williams Source Other was added to FAS.
Publications for gene FAS were updated from 7540117; 9028321; 9821419; 9927496; 10709732; 15459302; 8929361; 28668589; 26258116 to 26258116; 10709732; 15459302; 28668589; 8806292; 16537120; 16394653; 7540117; 26907631; 9927496; 9028321; 8929361; 9821419; 25451160; 22857792; 7511063; 22983577
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FASLG Eleanor Williams reviewed gene: FASLG: Rating: ; Mode of pathogenicity: ; Publications: 25451160, 7511063, 16537120, 22857792, 8806292, 22983577, 16394653, 26907631; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 FAS Eleanor Williams reviewed gene: FAS: Rating: ; Mode of pathogenicity: ; Publications: 25451160, 7511063, 16537120, 22857792, 8806292, 22983577, 16394653, 26907631; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.13 TGFBR2 Louise Daugherty gene: TGFBR2 was added
gene: TGFBR2 was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: TGFBR2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TGFBR2 were set to 32048120; 32086639
Phenotypes for gene: TGFBR2 were set to Recurrent respiratory infections, eczema, food allergies, hyperextensible joints, scoliosis, retention of primary teeths, aortic anuerysms; ALPS-FAS; Combined immunodeficiencies with associated or syndromic features
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FASLG Louise Daugherty commented on gene: FASLG: 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FAS Louise Daugherty commented on gene: FAS: 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FASLG Louise Daugherty commented on gene: FASLG: 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FAS Louise Daugherty commented on gene: FAS: 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FASLG Kimberly Gilmour reviewed gene: FASLG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FAS Kimberly Gilmour reviewed gene: FAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FASLG Tracy Briggs reviewed gene: FASLG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 FAS Tracy Briggs reviewed gene: FAS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 FASLG Louise Daugherty Source NHS GMS was added to FASLG.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 FAS Louise Daugherty Source NHS GMS was added to FAS.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 FASLG Louise Daugherty Source North West GLH was added to FASLG.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 FAS Louise Daugherty Source North West GLH was added to FAS.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 FASLG Louise Daugherty Source London North GLH was added to FASLG.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 FAS Louise Daugherty Source London North GLH was added to FAS.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.19 RAC2 Louise Daugherty commented on gene: RAC2: PMID: 10961859 reported functional studies demonstrating that the D57N mutant behaves in a dominant-negative fashion at the cellular level.
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty commented on gene: FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty commented on gene: FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty marked gene: FASLG as ready
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty marked gene: FAS as ready
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Sophie Hambleton reviewed gene: FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Sophie Hambleton reviewed gene: FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty commented on gene: FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty edited their review of gene: FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty classified FASLG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty classified FAS as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty edited their review of gene: FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty commented on FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty commented on FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty commented on FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty commented on FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty commented on FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty commented on FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FASLG Louise Daugherty reviewed FASLG
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty reviewed FAS
Primary immunodeficiency or monogenic inflammatory bowel disease FAS Louise Daugherty Added gene to panel