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Autoinflammatory Disorders v1.76 Bryony Thompson Panel name changed from Systemic Autoinflammatory Disease_Periodic Fever to Autoinflammatory Disorders
List of related panels changed from Fever HP:0001945 to Fever HP:0001945;Systemic autoinflammation HP:0033428
Autoinflammatory Disorders v1.54 IRAK2 Zornitza Stark Phenotypes for gene: IRAK2 were changed from Immune dysregulation, no OMIM # to Immune dysregulation, MONDO:0957790, IRAK2-related
Autoinflammatory Disorders v1.53 IRAK2 Zornitza Stark reviewed gene: IRAK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation, MONDO:0957790, IRAK2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoinflammatory Disorders v1.52 PSTPIP1 Zornitza Stark Phenotypes for gene: PSTPIP1 were changed from Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome to Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia, MIMM# 601979; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Autoinflammatory Disorders v1.51 PSTPIP1 Zornitza Stark edited their review of gene: PSTPIP1: Changed phenotypes: Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia, MIMM# 601979, Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Autoinflammatory Disorders v1.51 PTCRA Zornitza Stark Phenotypes for gene: PTCRA were changed from Autoinflammatory syndrome, MONDO:0019751, PTCRA-related to Immunodeficiency 126, MIM# 620931
Autoinflammatory Disorders v1.50 REXO2 Zornitza Stark Phenotypes for gene: REXO2 were changed from type 1 interferonopathy to Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related
Autoinflammatory Disorders v1.48 REXO2 Zornitza Stark reviewed gene: REXO2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory Disorders v1.48 TBK1 Zornitza Stark Phenotypes for gene: TBK1 were changed from Immunodeficiency, MONDO:0021094, TBK1-related, AR; Autoinflammation to Autoinflammation with arthritis and vasculitis, MIM# 620880
Autoinflammatory Disorders v1.43 SHARPIN Zornitza Stark Phenotypes for gene: SHARPIN were changed from Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related to Autoinflammation with episodic fever and immune dysregulation, MIM# 620795
Autoinflammatory Disorders v1.40 SHARPIN Zornitza Stark Phenotypes for gene: SHARPIN were changed from recurrent fever to Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related
Autoinflammatory Disorders v1.38 SHARPIN Zornitza Stark reviewed gene: SHARPIN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory Disorders v1.37 PTCRA Zornitza Stark gene: PTCRA was added
gene: PTCRA was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCRA were set to 38422122
Phenotypes for gene: PTCRA were set to Autoinflammatory syndrome, MONDO:0019751, PTCRA-related
Review for gene: PTCRA was set to GREEN
Added comment: PMID:38422122 reported the identification of 10 individuals from seven kindreds from four different ethnicities with biallelic PTCRA variants (homozygous in five kindreds and compound heterozygous in two kindreds).

Six of these 10 patients were clinically asymptomatic at their most recent evaluation, while other four patients displayed infection, lymphoproliferation, and/or autoimmunity with an onset during their teens or in adulthood. One of these patients died from SARS-CoV-2 pneumonia at the age of 24 years. Patient 9 had a small thymus on MRI at the age of 2 years, whereas P5 and P6 had no visible thymus at the ages of 13 and 8 years, respectively. Three of the nine patients with pLOF PTCRA variants tested were found to produce autoantibodies, several of which were associated with clinical manifestations. Anti-thyroid autoantibodies and/or clinically overt thyroiditis were found in three of the nine patients. P7, who suffered from recurrent herpes infections, had autoantibodies against type I interferons.

Two of those identified variants are hypomorphic and are associated with autoimmunity. In addition, there is extensive functional and epidemiological data available.
Sources: Literature
Autoinflammatory Disorders v1.36 SHARPIN Peter McNaughton gene: SHARPIN was added
gene: SHARPIN was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHARPIN were set to PMID: 38609546
Phenotypes for gene: SHARPIN were set to recurrent fever
Review for gene: SHARPIN was set to GREEN
Added comment: Two unrelated patients with homozygous frameshift variants presenting with:
P1 - recurrent fever, parotitis, joint inflammation, colitis and chronic otitis media necessitating tympanoplasty
P2 - recurrent fever episodes with lymphadenopathy and vomiting every 2–3 weeks.

Extensive functional data and mouse model.
Sources: Literature
Autoinflammatory Disorders v1.36 PSMA5 Zornitza Stark Phenotypes for gene: PSMA5 were changed from PRAAS/CANDLE to Inborn error of immunity, MONDO:0003778, PSMA5-related; PRAAS/CANDLE
Autoinflammatory Disorders v1.32 SIRT1 Zornitza Stark gene: SIRT1 was added
gene: SIRT1 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIRT1 were set to 23473037
Phenotypes for gene: SIRT1 were set to autoimmune disease, MONDO:0007179, SIRT1-related
Review for gene: SIRT1 was set to RED
Added comment: PMID:23473037 reported the identification of a missense SIRT1 variant (p.Leu107Pro) in five members of a single family and all five of them had autoimmune disorder, four had type I diabetes and one had ulcerative colitis.
Sources: Literature
Autoinflammatory Disorders v1.29 RNF31 Zornitza Stark gene: RNF31 was added
gene: RNF31 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Expert Review
Mode of inheritance for gene: RNF31 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF31 were set to 26008899; 30936877
Phenotypes for gene: RNF31 were set to Immunodeficiency 115 with autoinflammation, MIM# 620632
Review for gene: RNF31 was set to AMBER
Added comment: Two unrelated individuals reported.
Sources: Expert Review
Autoinflammatory Disorders v1.22 DDX58 Zornitza Stark Phenotypes for gene: DDX58 were changed from Lupus Nephritis to Lupus Nephritis, MONDO:0005556, DDX58-related
Autoinflammatory Disorders v1.20 DDX58 Chirag Patel gene: DDX58 was added
gene: DDX58 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: DDX58 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX58 were set to PMID: 36261300
Phenotypes for gene: DDX58 were set to Lupus Nephritis
Review for gene: DDX58 was set to GREEN
gene: DDX58 was marked as current diagnostic
Added comment: WES in cohort of lupus nephritis patients found a novel DDX58 pathogenic variant (R109C) in 5 unrelated families. The DDX58 R109C variant is a gain-of-function mutation, elevating type I IFN signaling due to reduced autoinhibition, which leads to RIG-I hyperactivation, increased RIG-I K63 ubiquitination, and MAVS aggregation. Transcriptome analysis revealed an increased IFN signature in patient monocytes. Initiation of JAK inhibitor therapy (baricitinib 2 mg/d) effectively suppressed the IFN signal in one patient.
Sources: Literature
Autoinflammatory Disorders v1.16 IL36RN Zornitza Stark Phenotypes for gene: IL36RN were changed from Psoriasis 14, pustular, MIM# 614204 to Psoriasis 14, pustular, MIM# 614204; Autoinflammatory syndrome, MONDO:0019751, IL36RN-related
Autoinflammatory Disorders v1.14 IRAK4 Zornitza Stark Phenotypes for gene: IRAK4 were changed from neuroinflammation, systemic autoinflammation, splenomegaly, and anemia to Autoinflammatory syndrome, MONDO:0019751, IRAK4-related
Autoinflammatory Disorders v1.12 IRAK4 Zornitza Stark reviewed gene: IRAK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome, MONDO:0019751, IRAK4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory Disorders v1.12 IRAK4 Peter McNaughton gene: IRAK4 was added
gene: IRAK4 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: IRAK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IRAK4 were set to PMID: 37744344
Phenotypes for gene: IRAK4 were set to neuroinflammation, systemic autoinflammation, splenomegaly, and anemia
Review for gene: IRAK4 was set to GREEN
Added comment: 5 patients from 2 unrelated kindreds with bi-allelic mutations in IRAK4, resulting in a severe autoinflammatory phenotype without overt immune deficiency, presenting with fever without infection, increased inflammatory markers, massive splenomegaly, transfusion dependent anemia; and severe neuroinflammation in 3/5 cases.
Sources: Literature
Autoinflammatory Disorders v1.12 RELA Zornitza Stark Marked gene: RELA as ready
Autoinflammatory Disorders v1.12 RELA Zornitza Stark Gene: rela has been classified as Green List (High Evidence).
Autoinflammatory Disorders v1.12 RELA Zornitza Stark Phenotypes for gene: RELA were changed from periodic fever, inflammatory bowel disease, JIA to Mucocutaneous ulceration, chronic, MIM# 618287; periodic fever, inflammatory bowel disease, JIA
Autoinflammatory Disorders v1.11 RELA Zornitza Stark Classified gene: RELA as Green List (high evidence)
Autoinflammatory Disorders v1.11 RELA Zornitza Stark Gene: rela has been classified as Green List (High Evidence).
Autoinflammatory Disorders v1.10 RELA Zornitza Stark reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory Disorders v1.9 RELA Peter McNaughton gene: RELA was added
gene: RELA was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RELA were set to PMID: 37273177
Phenotypes for gene: RELA were set to periodic fever, inflammatory bowel disease, JIA
Review for gene: RELA was set to GREEN
Added comment: Dominant negative RELA mutations in six patients from five unrelated families. Phenotypic overlap with RELA haploinsufficiency - chronic mucocutaneous ulcerations and autoimmune hematological disorders such as immune thrombocytopenia (ITP) and neutropenia. Patients with RELA DN mutations additionally presented periodic fever, inflammatory bowel diseases (IBDs), juvenile idiopathic arthritis (JIA), and skin involvement.
Sources: Literature
Autoinflammatory Disorders v1.6 STAT4 Melanie Marty gene: STAT4 was added
gene: STAT4 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: STAT4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT4 were set to PMID: 37256972
Phenotypes for gene: STAT4 were set to Disabling pansclerotic morphea of childhood MIM#620443
Mode of pathogenicity for gene: STAT4 was set to Other
Review for gene: STAT4 was set to GREEN
Added comment: Baghdassarian et al (2023) Four patients from three unrelated families with disabling pansclerotic morphea (DPM, a rare inflammatory disorder), 3 x het missense variants identified, AD inheritance. All 4 patients had disease onset before 5 years of age, with signs of mucosal ulcerations and skin sclerosis. These variants occur in the SH2 domain. Functional studies showed a gain of function effect for these variants.
Sources: Literature
Autoinflammatory Disorders v1.6 PMVK Zornitza Stark Phenotypes for gene: PMVK were changed from Autoinflammation to Autoinflammatory syndrome, MONDO:0019751, PMVK-related
Autoinflammatory Disorders v1.4 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Autoinflammatory Disorders v1.3 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from Autoinflammatory syndrome MONDO:0019751, CEBPE-related to Immunodeficiency 108 with autoinflammation , MIM# 260570
Autoinflammatory Disorders v1.2 FBXW11 Zornitza Stark Phenotypes for gene: FBXW11 were changed from Autoinflammation to Autoinflammatory disorder MONDO:0019751, FBXW11-related
Autoinflammatory Disorders v1.0 FBXW11 Zornitza Stark reviewed gene: FBXW11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory disorder MONDO:0019751, FBXW11-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory Disorders v0.167 Zornitza Stark List of related panels changed from to Fever HP:0001945
Autoinflammatory Disorders v0.166 DPP9 Zornitza Stark Phenotypes for gene: DPP9 were changed from recurrent fevers; repeated infections; herpes susceptibility; cytopaenias to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopaenias
Autoinflammatory Disorders v0.164 DPP9 Peter McNaughton gene: DPP9 was added
gene: DPP9 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPP9 were set to PMID: 36112693
Phenotypes for gene: DPP9 were set to recurrent fevers; repeated infections; herpes susceptibility; cytopaenias
Review for gene: DPP9 was set to GREEN
Added comment: Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopaenias.
Sources: Literature
Autoinflammatory Disorders v0.163 SAT1 Ee Ming Wong gene: SAT1 was added
gene: SAT1 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: SAT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SAT1 were set to 25977808
Phenotypes for gene: SAT1 were set to Systemic lupus erythematosus, MONDO:0007915, SAT1-related
Penetrance for gene: SAT1 were set to unknown
Review for gene: SAT1 was set to AMBER
gene: SAT1 was marked as current diagnostic
Added comment: - Two SAT1 loss of function variants reported in four SLE males across two American-African families, inherited from their unaffected mothers
- Using a minigene assay, the p.(Asp40Tyr) variant was shown to result in aberrant splicing
- Hemizygous knock-in male mice and homozygous female mice carrying the p.(Glu92Leufs*6) variant spontaneously developed lupus-like autoimmune disease, including splenomegaly, glomerular infiltration of leukocytes, proteinuria and elevated type I interferon scores
Sources: Literature
Autoinflammatory Disorders v0.163 CEBPE Zornitza Stark Phenotypes for gene: CEBPE were changed from Autoinflammation to Autoinflammatory syndrome MONDO:0019751, CEBPE-related
Autoinflammatory Disorders v0.161 TBK1 Zornitza Stark Phenotypes for gene: TBK1 were changed from Autoinflammation to Immunodeficiency, MONDO:0021094, TBK1-related, AR; Autoinflammation
Autoinflammatory Disorders v0.156 TBK1 Peter McNaughton gene: TBK1 was added
gene: TBK1 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: TBK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBK1 were set to PMID: 34363755
Phenotypes for gene: TBK1 were set to Autoinflammation
Review for gene: TBK1 was set to GREEN
Added comment: 4 individuals from 3 unrelated families with biallelic LOF mutations with early onset autoinflammatory syndrome without susceptibility to viral infection.
Sources: Literature
Autoinflammatory Disorders v0.152 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammation to Autoinflammatory syndrome, MONDO:0019751, HCK-related
Autoinflammatory Disorders v0.149 IKBKG Zornitza Stark gene: IKBKG was added
gene: IKBKG was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Expert list
Mode of inheritance for gene: IKBKG was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IKBKG were set to 31874111; 35289316
Phenotypes for gene: IKBKG were set to Autoinflammatory disease, systemic, X-linked, MIM# 301081
Review for gene: IKBKG was set to GREEN
Added comment: X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature.

6 unrelated boys and a girl reported. All variants resulted in absence of the domain encoded by exon 5 (NEMOdelEx5).

Note variants in this gene are associated with immunodeficiency +/- ectodermal features.
Sources: Expert list
Autoinflammatory Disorders v0.144 PSTPIP1 Zornitza Stark Phenotypes for gene: PSTPIP1 were changed from to Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Autoinflammatory Disorders v0.141 PSTPIP1 Zornitza Stark reviewed gene: PSTPIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11971877, 34938582, 34778321, 34745107, 34492165, 34047005; Phenotypes: Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory Disorders v0.114 C2orf69 Zornitza Stark gene: C2orf69 was added
gene: C2orf69 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency-53 (COXPD53), MIM#619423
Review for gene: C2orf69 was set to GREEN
Added comment: PMID 34038740: 20 affected children from 8 unrelated families reported, presenting with fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. Endogenous C2ORF69 was found to be (1) loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. Zebrafish model.

PMID 33945503: 8 individuals from 5 families reported with muscle hypotonia, developmental delay, progressive microcephaly, and brain MRI abnormalities. Age at onset ranged from birth to 6 months of age. Six patients had vision impairment, liver abnormalities, inflammation/inflammatory arthritis, and 5 patients had seizures.
Sources: Literature
Autoinflammatory Disorders v0.94 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Relapsing HLH to Relapsing HLH; Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Autoinflammatory Disorders v0.93 RC3H1 Zornitza Stark edited their review of gene: RC3H1: Changed phenotypes: Relapsing HLH, Hemophagocytic lymphohistiocytosis, familial, 6 618998
Autoinflammatory Disorders v0.77 RC3H1 Zornitza Stark changed review comment from: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data.
Sources: Literature; to: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data including mouse model.
Sources: Literature
Autoinflammatory Disorders v0.77 RC3H1 Zornitza Stark gene: RC3H1 was added
gene: RC3H1 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: RC3H1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RC3H1 were set to 31636267
Phenotypes for gene: RC3H1 were set to Relapsing HLH
Review for gene: RC3H1 was set to RED
Added comment: Single individual with bi-allelic LoF variant and relapsing HLH reported, some functional data.
Sources: Literature
Autoinflammatory Disorders v0.74 CDC42 Zornitza Stark changed review comment from: PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737
Sources: Literature; to: PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Yet another individual in PMID 32231661 with different de novo variant, p.Cys81Tyr who in addition developed haematological malignancy and also had syndromic features, including ID. Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737
Sources: Literature
Autoinflammatory Disorders v0.73 CDC42 Zornitza Stark gene: CDC42 was added
gene: CDC42 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC42 were set to 31601675; 32303876
Phenotypes for gene: CDC42 were set to Neonatal-onset cytopaenia with dyshaematopoiesis; autoinflammation; rash; HLH
Review for gene: CDC42 was set to GREEN
Added comment: PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737
Sources: Literature
Autoinflammatory Disorders v0.70 STAT2 Zornitza Stark gene: STAT2 was added
gene: STAT2 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: STAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAT2 were set to 31836668; 32092142
Review for gene: STAT2 was set to GREEN
Added comment: Three individuals from two unrelated families reported with bi-allelic GoF variants and severe auto inflammatory disease. Functional data. Note gene is already associated with other immune phenotypes.
Sources: Literature
Autoinflammatory Disorders v0.68 ALPK1 Zornitza Stark gene: ALPK1 was added
gene: ALPK1 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to 31053777
Phenotypes for gene: ALPK1 were set to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome
Review for gene: ALPK1 was set to AMBER
Added comment: Three unrelated families reported. One of the variants segregated in four affected individuals in one family and another was found to be de novo. The third variant however was not segregated, and is also present in 18 individuals in gnomad. Hence the evidence for variant pathogenicity in this third case is not compelling.
Sources: Literature
Autoinflammatory Disorders v0.40 HAVCR2 Zornitza Stark gene: HAVCR2 was added
gene: HAVCR2 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Expert list
Mode of inheritance for gene: HAVCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HAVCR2 were set to 30374066; 30792187
Phenotypes for gene: HAVCR2 were set to T-cell lymphoma, subcutaneous panniculitis-like, MIM# 618398
Review for gene: HAVCR2 was set to GREEN
Added comment: Over 20 unrelated individuals reported, note germline confirmation in only a few. Some variants are recurrent: c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met).
Sources: Expert list
Autoinflammatory Disorders v0.36 USP18 Zornitza Stark changed review comment from: Two unrelated families reported.
Sources: Expert list; to: Three unrelated families reported. Note cryptic 3' deletion identified in one.
Sources: Expert list
Autoinflammatory Disorders v0.34 USP18 Zornitza Stark gene: USP18 was added
gene: USP18 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Expert list
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to 31940699; 27325888
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2, MIM# 617397
Review for gene: USP18 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert list
Autoinflammatory Disorders v0.32 POLA1 Zornitza Stark gene: POLA1 was added
gene: POLA1 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Expert list
Mode of inheritance for gene: POLA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: POLA1 were set to 27019227
Phenotypes for gene: POLA1 were set to Pigmentary disorder, reticulate, with systemic manifestations, X-linked, MIM# 301220
Review for gene: POLA1 was set to GREEN
Added comment: 12 unrelated families with same g.24744696A-G transition (NC_000023.10, g.24744696A-G) in intron 13 of the POLA1 gene, resulting the introduction of a novel exon (exon 13a) into the transcript. Two of the families shared the same haplotype, indicative of founder effect but rest thought to have arisen independently, including at least one de novo variant.
Sources: Expert list