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Inflammatory bowel disease v0.113 HSPA1L Zornitza Stark gene: HSPA1L was added
gene: HSPA1L was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: HSPA1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPA1L were set to 28126021
Phenotypes for gene: HSPA1L were set to inflammatory bowel disease, MONDO:0005265, HSPA1L-related
Review for gene: HSPA1L was set to AMBER
Added comment: PMID:28126021 reported the identification of a heterozygous de novo variant (p.Ser277Leu) in HSPA1L in a patient with inflammatory bowel disease. In addition, five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) were identified in six patients from a cohort of 136 IBD patients with WES data. Functional studies showed that all six HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.

However, the variants identified are present at relatively high frequencies in gnomad V4, in particular p.Thr267Ile is present in 281 individuals, and the p.Ala268Thr is present in 4,753 individuals.
Sources: Literature
Inflammatory bowel disease v0.110 FMNL2 Zornitza Stark gene: FMNL2 was added
gene: FMNL2 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: FMNL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FMNL2 were set to 34043722
Phenotypes for gene: FMNL2 were set to inflammatory bowel disease, MONDO:0005265, FMNL2-related
Review for gene: FMNL2 was set to RED
Added comment: A patient was reported with a de novo heterozygous FMNL2 variant (p.Leu136Pro) and with severe very early onset inflammatory bowel disease (IBD). The functional characterisation of this variant showed that FMNL2 L136P protein displayed subcellular mislocalisation and deregulated protein autoinhibition indicating gain-of-function mechanism (PMID:34043722).
Sources: Literature
Inflammatory bowel disease v0.109 ANKZF1 Zornitza Stark Phenotypes for gene: ANKZF1 were changed from Infantile-onset inflammatory bowel disease to Infantile-onset inflammatory bowel disease, MONDO:0005265, ANKZF1-related
Inflammatory bowel disease v0.108 ALPI Zornitza Stark Phenotypes for gene: ALPI were changed from Inflammatory bowel disease to Inflammatory bowel disease, MONDO:0005265, ALPI-related
Inflammatory bowel disease v0.107 ALPI Zornitza Stark edited their review of gene: ALPI: Changed phenotypes: Inflammatory bowel disease, MONDO:0005265, ALPI-related
Inflammatory bowel disease v0.105 RELA Zornitza Stark changed review comment from: Additional 6 individuals from two families reported.; to: Additional 6 individuals from five families reported.
Inflammatory bowel disease v0.105 RELA Zornitza Stark Marked gene: RELA as ready
Inflammatory bowel disease v0.105 RELA Zornitza Stark Gene: rela has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.105 RELA Zornitza Stark Phenotypes for gene: RELA were changed from Inflammatory bowel disease to Mucocutaneous ulceration, chronic, MIM# 618287; Inflammatory bowel disease
Inflammatory bowel disease v0.104 RELA Zornitza Stark Classified gene: RELA as Green List (high evidence)
Inflammatory bowel disease v0.104 RELA Zornitza Stark Gene: rela has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.103 RELA Zornitza Stark edited their review of gene: RELA: Added comment: Additional 6 individuals from two families reported.; Changed rating: GREEN; Changed publications: 37273177
Inflammatory bowel disease v0.103 RELA Zornitza Stark reviewed gene: RELA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inflammatory bowel disease v0.103 RELA Peter McNaughton gene: RELA was added
gene: RELA was added to Inflammatory bowel disease. 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 Inflammatory bowel disease
Review for gene: RELA was set to GREEN
Added comment: Patients with RELA DN mutations additionally presented periodic fever, inflammatory bowel diseases (IBDs), juvenile idiopathic arthritis (JIA), and skin involvement. Complete penetrance was observed for IBD
Sources: Literature
Inflammatory bowel disease v0.100 DKC1 Krithika Murali reviewed gene: DKC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32554502; Phenotypes: DKC1-related disorder - MONDO: 0100152; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Inflammatory bowel disease v0.93 DKC1 Chris Richmond gene: DKC1 was added
gene: DKC1 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: DKC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DKC1 were set to 21284747
Phenotypes for gene: DKC1 were set to Dyskeratosis congenita
Penetrance for gene: DKC1 were set to unknown
Review for gene: DKC1 was set to GREEN
gene: DKC1 was marked as current diagnostic
Added comment: 2 unrelated infants with infant-onset DKC - the most prominent clinical finding was the presence of a severe, chronic, non-infectious enteropathy leading to malabsorption and nutrient deficiencies . Histological abnormalities included inflammation and mucosal apoptosis (identical to gut GVHD) in the esophagus, small bowel, or colon. Phenotypic overlap with IBD. Review with Dr. Peter McNaughton (immunologist QCH).
Sources: Expert Review
Inflammatory bowel disease v0.88 PMM2 Sarah Pantaleo gene: PMM2 was added
gene: PMM2 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMM2 were set to 36773065
Phenotypes for gene: PMM2 were set to Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Penetrance for gene: PMM2 were set to Incomplete
Review for gene: PMM2 was set to RED
Added comment: “A specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.”

Cohort of patients affected by hyperinsulinaemic hypoglycaemia and ARPKD with a specific underlying variant in the PMM2 promoter. Three of these patients additionally developed IBD in childhood and manifest a distinctive pattern of gastric antral disease involvement.

The authors describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6 and 10 years of age. IBD was of variable severity at onset. The organ level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A).

All three patients have the same genotype, two pathogenic variants (ClinVar): A promoter variant, c.-167G>T, in trans with c.422G>A; p.(Arg141His). The promoter region is not covered in gnomAD. c.422G>A is in gnomAD v2 891 hets, v3 557 hets.

Functional studies: Protein expression of PMM2 and HNF4A assessed by immunohistochemistry for two patients. Patient 1 there appeared to be reduced protein expression compared to the control, especially in the gastric antrum and colon, but for patient 2, the expression profile closely matched the control.

Observation of intestinal inflammation and gastric antral foveolar hyperplasia in three patients with identical pathogenic genetic variants in the PMM2 locus, from independent kindreds, extends the previously reported spectrum of PMM2-related HI/ARPKD disease. It identifies PMM2 as a potential novel Mendelian association of early-onset IBD. Estimate low penetrance of IBD of 10% based on 30 patients in the literature.
Sources: Literature
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Phenotypes for gene: LY96 were changed from Colitis to Inborn error of immunity, MONDO:0003778, LY96-related; Colitis
Inflammatory bowel disease v0.86 LY96 Zornitza Stark reviewed gene: LY96: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, LY96-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.85 Zornitza Stark HPO terms changed from to Gastrointestinal inflammation, HP:0004386
List of related panels changed from to Gastrointestinal inflammation; HP:0004386
Inflammatory bowel disease v0.84 NOX1 Zornitza Stark Phenotypes for gene: NOX1 were changed from Inflammatory bowel disease to Inflammatory bowel disease, MONDO:0005265, NOX1-related
Inflammatory bowel disease v0.82 NOX1 Zornitza Stark reviewed gene: NOX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32064493; Phenotypes: Inflammatory bowel disease, MONDO:0005265, NOX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inflammatory bowel disease v0.82 DUOX2 Zornitza Stark Phenotypes for gene: DUOX2 were changed from Colitis to Inflammatory bowel disease, MONDO:0005265, DUOX2-related
Inflammatory bowel disease v0.80 SLCO2A1 Zornitza Stark Phenotypes for gene: SLCO2A1 were changed from Enteropathy to Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related; Enteropathy
Inflammatory bowel disease v0.78 SLCO2A1 Zornitza Stark reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Inflammatory bowel disease, MONDO:0005265, SLCO2A1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.61 TNFAIP3 Lavvina Thiyagarajan gene: TNFAIP3 was added
gene: TNFAIP3 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: TNFAIP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFAIP3 were set to 34030699, 33446651, 32521965, 31299923
Phenotypes for gene: TNFAIP3 were set to Inflammatory bowel disease; Crohn's disease; Autoinflammatory syndrome, familial, Behcet-like
Penetrance for gene: TNFAIP3 were set to unknown
Review for gene: TNFAIP3 was set to GREEN
Added comment: 4 unrelated individuals with inflammatory bowel disease and variants TNFAIP3 - haploinsufficiency suggested as disease mechanism.
Sources: Literature
Inflammatory bowel disease v0.48 ZAP70 Lavvina Thiyagarajan changed review comment from: Three unrelated cases described in the literature. 1) 2 siblings with compound heterozygous missense mutations in ZAP70 2) female infant with homozygous missense mutation in ZAP70 3) individual with VEOIBD and missense mutation in ZAP70 (zygosity not specified in paper, no specific details regarding variant outlined in paper) - PMID: 32819795); to: Three unrelated cases described in the literature. 1) 2 siblings with compound heterozygous missense mutations in ZAP70 2) female infant with homozygous missense mutation in ZAP70 3) individual with VEOIBD and missense mutation in ZAP70 (zygosity not specified in paper, no specific details regarding variant outlined in paper) - PMID: 32819795)
Inflammatory bowel disease v0.48 ZAP70 Lavvina Thiyagarajan changed review comment from: Three unrelated cases described in the literature. 1) 2 siblings with compound heterozygous missense mutations in ZAP70 2) female infant with homozygous missense mutation in ZAP70 3) individual with VEOIBD and missense mutation in ZAP70 (zygosity not specified in paper hence details of this case are unclear - PMID: 32819795); to: Three unrelated cases described in the literature. 1) 2 siblings with compound heterozygous missense mutations in ZAP70 2) female infant with homozygous missense mutation in ZAP70 3) individual with VEOIBD and missense mutation in ZAP70 (zygosity not specified in paper, no specific details regarding variant outlined in paper) - PMID: 32819795)
Inflammatory bowel disease v0.48 ZAP70 Lavvina Thiyagarajan edited their review of gene: ZAP70: Added comment: Three unrelated cases described in the literature. 1) 2 siblings with compound heterozygous missense mutations in ZAP70 2) female infant with homozygous missense mutation in ZAP70 3) individual with VEOIBD and missense mutation in ZAP70 (zygosity not specified in paper hence details of this case are unclear - PMID: 32819795); Changed publications: 26783323, 32819795, 32633164
Inflammatory bowel disease v0.47 ZAP70 Lavvina Thiyagarajan gene: ZAP70 was added
gene: ZAP70 was added to Inflammatory bowel disease. Sources: Other
Mode of inheritance for gene: ZAP70 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZAP70 were set to 26783323
Phenotypes for gene: ZAP70 were set to Autoimmune disease, multisystem, infantile-onset, 2; inflammatory colitis
Penetrance for gene: ZAP70 were set to Complete
Review for gene: ZAP70 was set to AMBER
Added comment: 1 family described - 2 siblings of unrelated Caucasian parents with clinical findings and compound heterozygous missense mutations in ZAP70.
Sources: Other
Inflammatory bowel disease v0.41 ANKZF1 Bryony Thompson gene: ANKZF1 was added
gene: ANKZF1 was added to Inflammatory bowel disease. Sources: Other
Mode of inheritance for gene: ANKZF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANKZF1 were set to 28302725
Phenotypes for gene: ANKZF1 were set to Infantile-onset inflammatory bowel disease
Review for gene: ANKZF1 was set to AMBER
Added comment: Two unrelated cases (1 homozygous and 1 compound heterozygous), and supporting in vitro and yeast assays indicating that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity.
Sources: Other
Inflammatory bowel disease v0.40 ALPI Lavvina Thiyagarajan changed review comment from: 2 unrelated individuals with inflammatory bowel disease. Some functional evidence. Additional recent publication in 2020 regarding ALPI but no new individuals described.; to: 2 unrelated individuals with inflammatory bowel disease. Some functional evidence. Additional recent publication (PMID: 32084423) in 2020 but no new individuals identified (patient described has previously been reported).
Inflammatory bowel disease v0.40 ALPI Lavvina Thiyagarajan changed review comment from: 3 unrelated individuals with inflammatory bowel disease. Some functional evidence. Additional (3rd) individual described in recent (2020) publication with bi-allelic variants in ALPI.; to: 2 unrelated individuals with inflammatory bowel disease. Some functional evidence. Additional recent publication in 2020 regarding ALPI but no new individuals described.
Inflammatory bowel disease v0.37 ALPI Lavvina Thiyagarajan changed review comment from: 1 individual with clinically diagnosed inflammatory IBD - causal evidence: genetic, functional, pathology (as per paper) - in addition to 2 unrelated individuals from previous review.
; to: 3 unrelated individuals with inflammatory bowel disease. Some functional evidence. Additional (3rd) individual described in recent (2020) publication with bi-allelic variants in ALPI.
Inflammatory bowel disease v0.37 ALPI Lavvina Thiyagarajan changed review comment from: 1 individual with clinically diagnosed inflammatory IBD - causal evidence: genetic, functional, pathology (as per paper); to: 1 individual with clinically diagnosed inflammatory IBD - causal evidence: genetic, functional, pathology (as per paper) - in addition to 2 unrelated individuals from previous review.
Inflammatory bowel disease v0.36 SLC9A3 Zornitza Stark gene: SLC9A3 was added
gene: SLC9A3 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: SLC9A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC9A3 were set to 26358773; 33346580
Phenotypes for gene: SLC9A3 were set to Diarrhoea 8, secretory sodium, congenital 616868; Very Early Onset Inflammatory Bowel Disease
Review for gene: SLC9A3 was set to AMBER
Added comment: Described as a monogenic cause of VEOIBD. 2 patients from unrelated families in a series of 9 cases with SLC9A3-related congenital sodium diarrhoea developed intestinal inflammation/IBD (PMID: 26358773). GWAS have indicated a strong association between SLC9A3 and IBD, and there are supportive mouse models (reviewed in PMID: 26358773).Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580).
Sources: Expert Review
Inflammatory bowel disease v0.12 ADAM17 Zornitza Stark gene: ADAM17 was added
gene: ADAM17 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: ADAM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM17 were set to 22010916; 29560122; 26683521; 25804906
Phenotypes for gene: ADAM17 were set to Inflammatory skin and bowel disease, neonatal, 1, MIM# 614328; Recurrent infections
Review for gene: ADAM17 was set to GREEN
Added comment: Three unrelated families reported, inflammatory bowel disease was prominent in two; support from mouse model.
Sources: Expert Review
Inflammatory bowel disease v0.10 TRIM22 Zornitza Stark gene: TRIM22 was added
gene: TRIM22 was added to Inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: TRIM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM22 were set to 26836588
Phenotypes for gene: TRIM22 were set to Inflammatory bowel disease
Review for gene: TRIM22 was set to GREEN
Added comment: Three unrelated families reported with bi-allelic variants in this gene, and very early onset IBD, some functional data.
Sources: Expert list
Inflammatory bowel disease v0.8 ALPI Zornitza Stark gene: ALPI was added
gene: ALPI was added to Inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: ALPI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALPI were set to 29567797
Phenotypes for gene: ALPI were set to Inflammatory bowel disease
Review for gene: ALPI was set to AMBER
Added comment: Two unrelated individuals, some functional data.
Sources: Expert list
Inflammatory bowel disease v0.6 TGFB1 Zornitza Stark gene: TGFB1 was added
gene: TGFB1 was added to Inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: TGFB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TGFB1 were set to 29483653
Phenotypes for gene: TGFB1 were set to Inflammatory bowel disease, immunodeficiency, and encephalopathy, MIM# 618213
Review for gene: TGFB1 was set to AMBER
Added comment: Three individuals from two unrelated families reported. DD/ID and seizures in addition to IBD/immunodeficiency.
Sources: Expert list