From 78ec807cefdde9ed2098b22b032ce86bbe5c80da Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Sat, 17 Oct 2026 11:25:57 -0700 Subject: [PATCH 1/6] Review and deepen Ectodermal Dysplasia and Immunodeficiency 2 (MONDO:0012806) --- ...splasia-and-immunodeficiency-2-review.yaml | 39 ++++ ...rmal_Dysplasia_and_Immunodeficiency_2.yaml | 200 +++++++++++++++++- 2 files changed, 238 insertions(+), 1 deletion(-) create mode 100644 history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml diff --git a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml new file mode 100644 index 00000000000..39cede00acf --- /dev/null +++ b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml @@ -0,0 +1,39 @@ +history_version: 1 +target: + kind: disorder + slug: Ectodermal_Dysplasia_and_Immunodeficiency_2 + path: kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml +session: + id: 2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review + timestamp: '2026-10-17T17:00:00Z' + actors: + - type: ai_agent + name: antigravity + model: claude-opus-4-6 + agent_tool: antigravity +links: + issues: [] + prs: [] + urls: [] +events: +- type: REVIEW + outcome: changed + sections: + - references + - classifications + - prevalence + - progression + - genetic + - pathophysiology + - phenotypes + - treatments + - diagnosis + - differential_diagnoses + summary: Deepen Ectodermal Dysplasia and Immunodeficiency 2 with NFKBIA GO:0019904 trigger wiring, causal + downstream edges, and diagnosis/differential sections + details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0019904 + (protein domain specific binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream + pathophysiology nodes to clinical phenotypes, added evidence for Sparse Hair and Antimicrobial Prophylaxis, + and added classifications, prevalence, progression, diagnosis, and differential_diagnoses sections. + + ' diff --git a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml index b94420c3f24..9ee00c5d2b4 100644 --- a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml +++ b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml @@ -24,7 +24,54 @@ disease_term: parents: - Primary immunodeficiency - Ectodermal dysplasia +references: +- reference: PMID:14523047 + title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." +- reference: PMID:15337789 + title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." +- reference: PMID:28597146 + title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." +- reference: PMID:28629746 + title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." +- reference: PMID:31683054 + title: "A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia." +- reference: PMID:35005117 + title: "A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response." +- reference: PMID:35748970 + title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee." +- reference: CGGV:assertion_3333d698-dd58-4601-80b9-1892f2893bdf-2025-02-10T170000.000Z + title: "NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive)" classifications: + harrisons_chapter: + - classification_value: IMMUNE_RHEUMATOLOGIC + evidence: + - reference: PMID:28597146 + reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: "Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)." + explanation: >- + Establishes EDA-ID2 as a primary combined immunodeficiency affecting + innate and adaptive immune signaling. + - classification_value: GENETICS_ENVIRONMENT_DISEASE + evidence: + - reference: PMID:28597146 + reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: "Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)." + explanation: >- + Confirms that EDA-ID2 is a monogenic autosomal dominant genetic disorder. + - classification_value: DERMATOLOGY + evidence: + - reference: PMID:15337789 + reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: "several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling" + explanation: >- + Confirms syndromic ectodermal dysplasia affecting skin, hair, sweat + glands, and teeth. iuis_category: classification_value: combined immunodeficiency with syndromic features notes: >- @@ -72,6 +119,41 @@ inheritance: explanation: >- Demonstrates somatic mosaicism in a parent as the mechanism of inherited transmission, with widely different clinical outcomes between father and son. +prevalence: +- population: Global published literature + measure_type: CASES_IN_LITERATURE + prevalence_class: ULTRA_RARE + notes: >- + Ultra-rare autosomal dominant inborn error of immunity; 14 unrelated + patients were reported between 2003 and 2017, with sparse additional cases + described subsequently. + evidence: + - reference: PMID:28597146 + reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: "Fourteen unrelated patients have been reported since the identification of the first case in 2003." + explanation: >- + Comprehensive literature review documents 14 unrelated cases reported + worldwide between 2003 and 2017. +progression: +- phase: Infancy + age_range: Infancy to early childhood + notes: >- + Patients present in early infancy with severe recurrent pyogenic, + mycobacterial, viral, and fungal infections alongside ectodermal dysplasia + signs; the disorder carries high early mortality without antimicrobial + prophylaxis, immunoglobulin replacement, and hematopoietic stem cell + transplantation. + evidence: + - reference: PMID:28597146 + reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: "In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT." + explanation: >- + Documents early infantile lethality without intervention and long-term + survival outcomes with prophylaxis or HSCT. has_subtypes: - name: Missense display_name: Missense mutations (S32/S36 region) @@ -93,6 +175,7 @@ genetic: id: hgnc:7797 label: NFKBIA association: CAUSATIVE + relationship_type: CAUSATIVE features: > Two classes of gain-of-function mutations: (i) missense mutations affecting S32, S36, or neighboring residues (majority of patients), and (ii) nonsense mutations @@ -149,6 +232,16 @@ pathophysiology: degradation. The mutant IkBa constitutively sequesters NF-kB dimers in the cytoplasm, abolishing NF-kB-dependent transcriptional activation in response to stimulation of TLRs, IL-1 receptors, TNF receptors, TCR, and BCR. + genes: + - preferred_term: NFKBIA + term: + id: hgnc:7797 + label: NFKBIA + molecular_functions: + - preferred_term: protein binding + term: + id: GO:0005515 + label: protein binding cell_types: - preferred_term: T cell term: @@ -159,6 +252,7 @@ pathophysiology: term: id: GO:0007249 label: canonical NF-kappaB signal transduction + modifier: DECREASED downstream: - target: Impaired T Cell Development and Function - target: Defective Innate Immune Signaling @@ -207,6 +301,11 @@ pathophysiology: term: id: GO:0042098 label: T cell proliferation + downstream: + - target: Lymphocytosis with Absent Memory T Cells + causal_link_type: DIRECT + - target: Recurrent Infections + causal_link_type: DIRECT evidence: - reference: PMID:14523047 reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." @@ -254,6 +353,11 @@ pathophysiology: term: id: GO:0002224 label: toll-like receptor signaling pathway + downstream: + - target: Recurrent Mycobacterial Infections + causal_link_type: DIRECT + - target: Recurrent Infections + causal_link_type: DIRECT evidence: - reference: PMID:14523047 reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." @@ -292,6 +396,13 @@ pathophysiology: term: id: GO:0042113 label: B cell activation + downstream: + - target: B Cell Deficiency + causal_link_type: DIRECT + - target: Agammaglobulinemia + causal_link_type: DIRECT + - target: Elevated IgM with Agammaglobulinemia + causal_link_type: DIRECT evidence: - reference: PMID:28597146 reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." @@ -325,6 +436,9 @@ pathophysiology: term: id: GO:0048535 label: lymph node development + downstream: + - target: Absent Peripheral Lymph Nodes + causal_link_type: DIRECT evidence: - reference: PMID:28629746 reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." @@ -361,6 +475,15 @@ pathophysiology: term: id: GO:0060788 label: ectodermal placode formation + downstream: + - target: Hypohidrosis + causal_link_type: DIRECT + - target: Sparse Hair + causal_link_type: DIRECT + - target: Conical Teeth + causal_link_type: DIRECT + - target: Periorbital Wrinkles + causal_link_type: DIRECT evidence: - reference: PMID:28597146 reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." @@ -415,6 +538,17 @@ phenotypes: term: id: HP:0002209 label: Sparse scalp hair + evidence: + - reference: PMID:28597146 + reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: >- + Thirteen patients had developmental features of EDA, the severity and + nature of which differed between cases. + explanation: >- + Confirms developmental ectodermal dysplasia manifestations including + sparse scalp hair across reported patients. - category: Dental name: Conical Teeth description: > @@ -676,6 +810,17 @@ treatments: term: id: NCIT:C15986 label: Pharmacotherapy + evidence: + - reference: PMID:15337789 + reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: >- + From the second infection onwards, Ig substitution was initiated together + with cotrimoxazole as P. carinii prophylaxis. + explanation: >- + Demonstrates clinical use of cotrimoxazole as Pneumocystis carinii + antimicrobial prophylaxis in an EDA-ID2 patient. - name: Immunoglobulin Replacement Therapy description: > Intravenous or subcutaneous immunoglobulin replacement for patients @@ -696,4 +841,57 @@ treatments: explanation: >- Demonstrates clinical use of immunoglobulin substitution and antimicrobial prophylaxis in managing an EDA-ID2 patient. -datasets: +diagnosis: +- name: NFKBIA Molecular Genetic Testing + description: >- + Targeted sequence analysis or exome/genome sequencing of NFKBIA to identify + heterozygous gain-of-function variants affecting the DSGxxS degron motif + (Ser32, Ser36, or adjacent residues) or producing N-terminally truncated + IkBa proteins resistant to signal-induced phosphorylation and degradation. + diagnosis_term: + preferred_term: molecular genetic testing + term: + id: NCIT:C15709 + label: Genetic Testing + evidence: + - reference: PMID:14523047 + reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: >- + an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous + missense mutation at serine 32 of IkappaBalpha + explanation: >- + Establishes identification of heterozygous NFKBIA (IkappaBalpha) mutations + at serine 32 as the molecular basis for diagnosing autosomal dominant + EDA-ID. +differential_diagnoses: +- name: X-Linked Ectodermal Dysplasia and Immunodeficiency 1 + description: >- + Caused by hemizygous hypomorphic mutations in IKBKG (NEMO), presenting with + overlapping anhidrotic ectodermal dysplasia and pyogenic/mycobacterial + susceptibility, but distinguished by X-linked inheritance and the absence + of the severe naive T-cell lymphocytosis and memory T-cell deficiency + characteristic of NFKBIA gain-of-function disease. + distinguishing_features: + - X-linked recessive inheritance via IKBKG (NEMO) rather than autosomal dominant NFKBIA gain-of-function + - Preserved memory T-cell development and in vitro TCR responsiveness compared to the severe naive T-cell block in EDA-ID2 + disease_term: + preferred_term: IKBKG-related immunodeficiency with or without ectodermal dysplasia + term: + id: MONDO:0100162 + label: IKBKG-related immunodeficiency with or without ectodermal dysplasia + evidence: + - reference: PMID:14523047 + reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: >- + AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell + immunodeficiency. Despite a marked blood lymphocytosis, there are no + detectable memory T cells in vivo, and naive T cells do not respond to + CD3-TCR activation in vitro. + explanation: >- + Distinguishes autosomal dominant EDA-ID2 from X-linked EDA-ID1 by the + unique severe T-cell immunodeficiency with blood lymphocytosis, absent + memory T cells, and impaired CD3-TCR activation. From ca545475535e95d59726e5bae63121e4397ac7b1 Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Sat, 17 Oct 2026 12:01:50 -0700 Subject: [PATCH 2/6] Fix CI validation findings for Ectodermal_Dysplasia_and_Immunodeficiency_2 --- kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml index 9ee00c5d2b4..547a299d74e 100644 --- a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml +++ b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml @@ -397,7 +397,7 @@ pathophysiology: id: GO:0042113 label: B cell activation downstream: - - target: B Cell Deficiency + - target: Decreased Circulating B Cell Count causal_link_type: DIRECT - target: Agammaglobulinemia causal_link_type: DIRECT @@ -657,7 +657,7 @@ phenotypes: Confirms lymphocytosis as a feature in some patients, along with dysfunctional T cells and absent gamma/delta T cells. - category: Immunological - name: B Cell Deficiency + name: Decreased Circulating B Cell Count description: > Profound reduction in circulating B cells, a universal finding in patients with IkBa gain-of-function mutations. From 89460218647e4b944e63b684ad7ebf7f2bb59783 Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Sat, 17 Oct 2026 23:34:39 -0700 Subject: [PATCH 3/6] Address review feedback for Ectodermal_Dysplasia_and_Immunodeficiency_2 (PR #14737) --- ...splasia-and-immunodeficiency-2-review.yaml | 25 +- ...rmal_Dysplasia_and_Immunodeficiency_2.yaml | 785 ++++++++---------- 2 files changed, 336 insertions(+), 474 deletions(-) diff --git a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml index 39cede00acf..617c560a7d0 100644 --- a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml +++ b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml @@ -13,27 +13,24 @@ session: agent_tool: antigravity links: issues: [] - prs: [] + prs: + - https://github.com/monarch-initiative/dismech/pull/14737 urls: [] events: - type: REVIEW outcome: changed sections: - - references - - classifications - - prevalence - - progression - - genetic - pathophysiology - phenotypes + - genetic - treatments - - diagnosis - - differential_diagnoses - summary: Deepen Ectodermal Dysplasia and Immunodeficiency 2 with NFKBIA GO:0019904 trigger wiring, causal - downstream edges, and diagnosis/differential sections - details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0019904 - (protein domain specific binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream - pathophysiology nodes to clinical phenotypes, added evidence for Sparse Hair and Antimicrobial Prophylaxis, - and added classifications, prevalence, progression, diagnosis, and differential_diagnoses sections. + summary: Deepen Ectodermal Dysplasia and Immunodeficiency 2 with GO:0140297 transcription factor binding grounding, AD EDA-ID-specific + PMID:28629746 phenotype evidence, four additional phenotypes, structured gene_disease_validity, and CHEBI:3770 therapeutic_agent. + details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0140297 (DNA-binding transcription + factor binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream pathophysiology nodes to clinical + phenotypes including Severe Combined Immunodeficiency, Mycobacterial Infections, Chronic Diarrhea, and Impaired Polysaccharide + Antibody Response, replaced generic ectodermal dysplasia snippets with AD EDA-ID-specific PMID:28629746 evidence, populated + gene_disease_validity: DEFINITIVE on NFKBIA and therapeutic_agent CHEBI:3770 on Antimicrobial Prophylaxis, and added classifications, + prevalence, progression, diagnosis, and differential_diagnoses sections. ' diff --git a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml index 547a299d74e..c22d954a69f 100644 --- a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml +++ b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml @@ -1,21 +1,13 @@ name: Ectodermal Dysplasia and Immunodeficiency 2 -creation_date: "2026-04-24T00:00:00Z" +creation_date: '2026-04-24T00:00:00Z' category: Mendelian synonyms: - EDA-ID2 - Anhidrotic ectodermal dysplasia with T-cell immunodeficiency, autosomal dominant - NFKBIA-related ectodermal dysplasia with immunodeficiency -description: > - Ectodermal dysplasia and immunodeficiency 2 (EDA-ID2) is a rare autosomal dominant - disorder caused by heterozygous gain-of-function mutations in NFKBIA, encoding the - NF-kB inhibitor IkBa. These mutations prevent phosphorylation at serines 32 and 36 - by the IKK complex, rendering IkBa resistant to ubiquitination and proteasomal - degradation, which results in constitutive inhibition of NF-kB signaling. - The disorder presents with anhidrotic ectodermal dysplasia features (hypohidrosis, - sparse hair, conical teeth) combined with severe immunodeficiency affecting both - innate and adaptive immunity. Patients are susceptible to pyogenic, mycobacterial, - fungal, and viral infections. Most mutations occur de novo, and the condition - carries high mortality without hematopoietic stem cell transplantation. +description: 'Ectodermal dysplasia and immunodeficiency 2 (EDA-ID2) is a rare autosomal dominant disorder caused by heterozygous gain-of-function mutations in NFKBIA, encoding the NF-kB inhibitor IkBa. These mutations prevent phosphorylation at serines 32 and 36 by the IKK complex, rendering IkBa resistant to ubiquitination and proteasomal degradation, which results in constitutive inhibition of NF-kB signaling. The disorder presents with anhidrotic ectodermal dysplasia features (hypohidrosis, sparse hair, conical teeth) combined with severe immunodeficiency affecting both innate and adaptive immunity. Patients are susceptible to pyogenic, mycobacterial, fungal, and viral infections. Most mutations occur de novo, and the condition carries high mortality without hematopoietic stem cell transplantation. + + ' disease_term: preferred_term: ectodermal dysplasia and immunodeficiency 2 term: @@ -26,67 +18,57 @@ parents: - Ectodermal dysplasia references: - reference: PMID:14523047 - title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. - reference: PMID:15337789 - title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. - reference: PMID:28597146 - title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' - reference: PMID:28629746 - title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." + title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. - reference: PMID:31683054 - title: "A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia." + title: A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia. - reference: PMID:35005117 - title: "A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response." + title: A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response. - reference: PMID:35748970 - title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee." + title: 'Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.' - reference: CGGV:assertion_3333d698-dd58-4601-80b9-1892f2893bdf-2025-02-10T170000.000Z - title: "NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive)" + title: NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive) classifications: harrisons_chapter: - classification_value: IMMUNE_RHEUMATOLOGIC evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: "Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)." - explanation: >- - Establishes EDA-ID2 as a primary combined immunodeficiency affecting - innate and adaptive immune signaling. + snippet: Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). + explanation: Establishes EDA-ID2 as a primary combined immunodeficiency affecting innate and adaptive immune signaling. - classification_value: GENETICS_ENVIRONMENT_DISEASE evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: "Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)." - explanation: >- - Confirms that EDA-ID2 is a monogenic autosomal dominant genetic disorder. + snippet: Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). + explanation: Confirms that EDA-ID2 is a monogenic autosomal dominant genetic disorder. - classification_value: DERMATOLOGY evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: "several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling" - explanation: >- - Confirms syndromic ectodermal dysplasia affecting skin, hair, sweat - glands, and teeth. + snippet: several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling + explanation: Confirms syndromic ectodermal dysplasia affecting skin, hair, sweat glands, and teeth. iuis_category: classification_value: combined immunodeficiency with syndromic features - notes: >- - IUIS 2022 phenotypic classification Table 2 (combined immunodeficiencies - with associated or syndromic features); NFKBIA-related ectodermal - dysplasia with immunodeficiency (EDA-ID2). + notes: IUIS 2022 phenotypic classification Table 2 (combined immunodeficiencies with associated or syndromic features); NFKBIA-related ectodermal dysplasia with immunodeficiency (EDA-ID2). evidence: - reference: PMID:35748970 - reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee." + reference_title: 'Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.' supports: SUPPORT evidence_source: OTHER - snippet: "We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee." - explanation: >- - EDA-ID2 is classified under IUIS Table 2 (combined immunodeficiency with - syndromic features) in the IUIS phenotypic IEI nosology. + snippet: We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. + explanation: EDA-ID2 is classified under IUIS Table 2 (combined immunodeficiency with syndromic features) in the IUIS phenotypic IEI nosology. inheritance: - name: Autosomal dominant inheritance inheritance_term: @@ -94,79 +76,57 @@ inheritance: term: id: HP:0000006 label: Autosomal dominant inheritance - description: > - Nearly all reported cases are de novo. One case of inheritance from a - parent with somatic mosaicism has been documented. - de_novo_rate: ">90%" + description: 'Nearly all reported cases are de novo. One case of inheritance from a parent with somatic mosaicism has been documented. + + ' + de_novo_rate: '>90%' evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - The mutation certainly or probably occurred de novo in 13 patients, - whereas it was inherited from a parent with somatic mosaicism in one - patient. - explanation: >- - Comprehensive review of 14 patients shows 13/14 had de novo mutations, - confirming autosomal dominant inheritance with very high de novo rate. + snippet: The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. + explanation: Comprehensive review of 14 patients shows 13/14 had de novo mutations, confirming autosomal dominant inheritance with very high de novo rate. - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - his father has the same mutation but displays complex mosaicism - explanation: >- - Demonstrates somatic mosaicism in a parent as the mechanism of inherited - transmission, with widely different clinical outcomes between father and son. + snippet: his father has the same mutation but displays complex mosaicism + explanation: Demonstrates somatic mosaicism in a parent as the mechanism of inherited transmission, with widely different clinical outcomes between father and son. prevalence: - population: Global published literature measure_type: CASES_IN_LITERATURE prevalence_class: ULTRA_RARE - notes: >- - Ultra-rare autosomal dominant inborn error of immunity; 14 unrelated - patients were reported between 2003 and 2017, with sparse additional cases - described subsequently. + notes: Ultra-rare autosomal dominant inborn error of immunity; 14 unrelated patients were reported between 2003 and 2017, with sparse additional cases described subsequently. evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: "Fourteen unrelated patients have been reported since the identification of the first case in 2003." - explanation: >- - Comprehensive literature review documents 14 unrelated cases reported - worldwide between 2003 and 2017. + snippet: Fourteen unrelated patients have been reported since the identification of the first case in 2003. + explanation: Comprehensive literature review documents 14 unrelated cases reported worldwide between 2003 and 2017. progression: - phase: Infancy age_range: Infancy to early childhood - notes: >- - Patients present in early infancy with severe recurrent pyogenic, - mycobacterial, viral, and fungal infections alongside ectodermal dysplasia - signs; the disorder carries high early mortality without antimicrobial - prophylaxis, immunoglobulin replacement, and hematopoietic stem cell - transplantation. + notes: Patients present in early infancy with severe recurrent pyogenic, mycobacterial, viral, and fungal infections alongside ectodermal dysplasia signs; the disorder carries high early mortality without antimicrobial prophylaxis, immunoglobulin replacement, and hematopoietic stem cell transplantation. evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: "In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT." - explanation: >- - Documents early infantile lethality without intervention and long-term - survival outcomes with prophylaxis or HSCT. + snippet: In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. + explanation: Documents early infantile lethality without intervention and long-term survival outcomes with prophylaxis or HSCT. has_subtypes: - name: Missense display_name: Missense mutations (S32/S36 region) - description: > - Point mutations at or adjacent to the S32/S36 phosphorylation sites. - Associated with higher mutant protein levels and more severe disease, - including full ectodermal dysplasia and profound immunodeficiency. + description: 'Point mutations at or adjacent to the S32/S36 phosphorylation sites. Associated with higher mutant protein levels and more severe disease, including full ectodermal dysplasia and profound immunodeficiency. + + ' - name: Truncation display_name: N-terminal truncation mutations - description: > - Nonsense mutations upstream of S32 with reinitiation of translation - downstream of S36, producing truncated IkBa lacking both phosphorylation - sites. Generally associated with less severe disease. + description: 'Nonsense mutations upstream of S32 with reinitiation of translation downstream of S36, producing truncated IkBa lacking both phosphorylation sites. Generally associated with less severe disease. + + ' genetic: - name: NFKBIA gene_term: @@ -176,72 +136,55 @@ genetic: label: NFKBIA association: CAUSATIVE relationship_type: CAUSATIVE - features: > - Two classes of gain-of-function mutations: (i) missense mutations affecting S32, - S36, or neighboring residues (majority of patients), and (ii) nonsense mutations - upstream from S32 associated with reinitiation of translation downstream from S36. - Missense mutations tend to produce more severe phenotypes due to higher levels of - gain-of-function protein. Genotype-phenotype correlation shows that point mutants - accumulate at higher levels and cause greater impairment of both canonical and - noncanonical NF-kB activity compared to truncation mutants. + features: 'Two classes of gain-of-function mutations: (i) missense mutations affecting S32, S36, or neighboring residues (majority of patients), and (ii) nonsense mutations upstream from S32 associated with reinitiation of translation downstream from S36. Missense mutations tend to produce more severe phenotypes due to higher levels of gain-of-function protein. Genotype-phenotype correlation shows that point mutants accumulate at higher levels and cause greater impairment of both canonical and noncanonical NF-kB activity compared to truncation mutants. + + ' evidence: - reference: PMID:28629746 - reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." + reference_title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Disease severity was greater in patients with IκBα point mutations than - in those with truncation mutations. IκBα point mutants were expressed at - significantly higher levels in transfectants compared with truncation mutants. - explanation: >- - Establishes genotype-phenotype correlation showing point mutations cause - more severe disease due to higher mutant protein levels. + snippet: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. + explanation: Establishes genotype-phenotype correlation showing point mutations cause more severe disease due to higher mutant protein levels. - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Eleven mutations, belonging to two groups, were identified: (i) missense - mutations affecting S32, S36, or neighboring residues (8 mutations, 11 - patients) and (ii) nonsense mutations upstream from S32 associated with - the reinitiation of translation downstream from S36 (3 mutations, 3 patients). - explanation: >- - Comprehensive review classifying all known NFKBIA gain-of-function mutations - into two functional groups. + snippet: 'Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients).' + explanation: Comprehensive review classifying all known NFKBIA gain-of-function mutations into two functional groups. - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous - missense mutation at serine 32 of IkappaBalpha - explanation: >- - Original report identifying the first NFKBIA gain-of-function mutation - at the critical S32 phosphorylation site. + snippet: an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha + explanation: Original report identifying the first NFKBIA gain-of-function mutation at the critical S32 phosphorylation site. - reference: CGGV:assertion_3333d698-dd58-4601-80b9-1892f2893bdf-2025-02-10T170000.000Z - reference_title: "NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive)" + reference_title: NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive) supports: SUPPORT evidence_source: OTHER - snippet: "NFKBIA | HGNC:7797 | ectodermal dysplasia and immunodeficiency 2 | MONDO:0012806 | AD | Definitive" + snippet: NFKBIA | HGNC:7797 | ectodermal dysplasia and immunodeficiency 2 | MONDO:0012806 | AD | Definitive explanation: ClinGen classifies the NFKBIA-ectodermal dysplasia and immunodeficiency 2 gene-disease relationship as definitive with autosomal dominant inheritance. + gene_disease_validity: + - validity_classification: DEFINITIVE + classified_by: CLINGEN + external_id: CGGV:assertion_3333d698-dd58-4601-80b9-1892f2893bdf-2025-02-10T170000.000Z + evidence: + - reference: CGGV:assertion_3333d698-dd58-4601-80b9-1892f2893bdf-2025-02-10T170000.000Z + reference_title: NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive) + supports: SUPPORT + evidence_source: OTHER + snippet: NFKBIA | HGNC:7797 | ectodermal dysplasia and immunodeficiency 2 | MONDO:0012806 | AD | Definitive + explanation: ClinGen SCID-CID Gene Curation Expert Panel classifies the autosomal dominant NFKBIA-ectodermal dysplasia and immunodeficiency 2 (MONDO:0012806) relationship as Definitive. pathophysiology: - name: Constitutive NF-kB Inhibition by Gain-of-Function IkBa - description: > - Gain-of-function mutations in NFKBIA prevent phosphorylation of IkBa at - serines 32 and 36 by the IKK complex, blocking ubiquitination and proteasomal - degradation. The mutant IkBa constitutively sequesters NF-kB dimers in the - cytoplasm, abolishing NF-kB-dependent transcriptional activation in response - to stimulation of TLRs, IL-1 receptors, TNF receptors, TCR, and BCR. + description: 'Gain-of-function mutations in NFKBIA prevent phosphorylation of IkBa at serines 32 and 36 by the IKK complex, blocking ubiquitination and proteasomal degradation. The mutant IkBa constitutively sequesters NF-kB dimers in the cytoplasm, abolishing NF-kB-dependent transcriptional activation in response to stimulation of TLRs, IL-1 receptors, TNF receptors, TCR, and BCR. + + ' genes: - preferred_term: NFKBIA term: id: hgnc:7797 label: NFKBIA - molecular_functions: - - preferred_term: protein binding - term: - id: GO:0005515 - label: protein binding cell_types: - preferred_term: T cell term: @@ -261,32 +204,27 @@ pathophysiology: - target: Ectodermal Dysplasia evidence: - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - This mutation is gain-of-function, as it enhances the inhibitory capacity of - IkappaBalpha by preventing its phosphorylation and degradation, and results - in impaired NF-kappaB activation. - explanation: >- - Original characterization of the gain-of-function mechanism by which mutant - IkBa resists degradation and constitutively inhibits NF-kB. + snippet: This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. + explanation: Original characterization of the gain-of-function mechanism by which mutant IkBa resists degradation and constitutively inhibits NF-kB. - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - All mutations enhanced the inhibitory activity of IκBα, by preventing its - phosphorylation on serine 32 or 36 and its subsequent degradation. - explanation: >- - Review confirming that all reported mutations share the same gain-of-function - mechanism of preventing IkBa phosphorylation. + snippet: All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. + explanation: Review confirming that all reported mutations share the same gain-of-function mechanism of preventing IkBa phosphorylation. + molecular_functions: + - preferred_term: DNA-binding transcription factor binding + term: + id: GO:0140297 + label: DNA-binding transcription factor binding + modifier: INCREASED - name: Impaired T Cell Development and Function - description: > - NF-kB signaling is essential for T-cell development, activation, and survival. - Constitutive IkBa-mediated NF-kB inhibition results in a unique T-cell - immunodeficiency characterized by lymphocytosis with absence of memory T cells - and failure of naive T cells to respond to TCR stimulation. + description: 'NF-kB signaling is essential for T-cell development, activation, and survival. Constitutive IkBa-mediated NF-kB inhibition results in a unique T-cell immunodeficiency characterized by lymphocytosis with absence of memory T cells and failure of naive T cells to respond to TCR stimulation. + + ' cell_types: - preferred_term: T cell term: @@ -306,35 +244,35 @@ pathophysiology: causal_link_type: DIRECT - target: Recurrent Infections causal_link_type: DIRECT + - target: Chronic Mucocutaneous Candidiasis + description: Impaired T-cell immunity and defective IL-17/NF-kB-dependent mucosal defense predispose to chronic mucocutaneous candidiasis. + causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES + - target: Pneumocystis jirovecii Pneumonia + description: Profound functional T-cell immunodeficiency predisposes to opportunistic Pneumocystis jirovecii pneumonia. + causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES + - target: Chronic Diarrhea + description: Combined T-cell and mucosal immune deficiency leads to recurrent enteropathy and chronic diarrhea. + causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES + - target: Decreased Gamma-Delta T Cell Proportion + description: Constitutive NF-kB inhibition impairs development or maintenance of circulating gamma-delta T cells. + causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES evidence: - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell - immunodeficiency. Despite a marked blood lymphocytosis, there are no - detectable memory T cells in vivo, and naive T cells do not respond to - CD3-TCR activation in vitro. - explanation: >- - Demonstrates the distinctive T-cell dysfunction pattern in EDA-ID2: - lymphocytosis with absent memory T cells and unresponsive naive T cells. + snippet: AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. + explanation: 'Demonstrates the distinctive T-cell dysfunction pattern in EDA-ID2: lymphocytosis with absent memory T cells and unresponsive naive T cells.' - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - T cell receptor-mediated proliferation was also impaired. - explanation: >- - Independent confirmation of defective TCR-mediated T cell proliferation - in a patient with the S32I IkBa mutation. + snippet: T cell receptor-mediated proliferation was also impaired. + explanation: Independent confirmation of defective TCR-mediated T cell proliferation in a patient with the S32I IkBa mutation. - name: Defective Innate Immune Signaling - description: > - NF-kB is a central mediator of innate immune responses downstream of - Toll-like receptors. Constitutive IkBa inhibition impairs monocyte and - macrophage activation, with absent IL-12 production in response to TLR - stimulation and impaired NF-kB nuclear translocation, leading to - susceptibility to mycobacterial and other intracellular pathogens. + description: 'NF-kB is a central mediator of innate immune responses downstream of Toll-like receptors. Constitutive IkBa inhibition impairs monocyte and macrophage activation, with absent IL-12 production in response to TLR stimulation and impaired NF-kB nuclear translocation, leading to susceptibility to mycobacterial and other intracellular pathogens. + + ' cell_types: - preferred_term: macrophage term: @@ -360,32 +298,21 @@ pathophysiology: causal_link_type: DIRECT evidence: - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, - and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily - members and severe bacterial diseases - explanation: >- - Demonstrates broad impairment of innate immune signaling downstream of - multiple receptor superfamilies due to NF-kB inhibition. + snippet: impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases + explanation: Demonstrates broad impairment of innate immune signaling downstream of multiple receptor superfamilies due to NF-kB inhibition. - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Monocytes did not produce interleukin 12p40 upon stimulation with various - TLR stimuli and nuclear translocation of NF-kappaB was impaired. - explanation: >- - Directly demonstrates defective monocyte function with absent IL-12 - production and impaired NF-kB nuclear translocation. + snippet: Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-kappaB was impaired. + explanation: Directly demonstrates defective monocyte function with absent IL-12 production and impaired NF-kB nuclear translocation. - name: B Cell Deficiency - description: > - NF-kB signaling is required for B-cell development and function. Patients - with IkBa gain-of-function mutations have profound B-cell deficiency with - agammaglobulinemia or hyper-IgM phenotype, reflecting defective class-switch - recombination. + description: 'NF-kB signaling is required for B-cell development and function. Patients with IkBa gain-of-function mutations have profound B-cell deficiency with agammaglobulinemia or hyper-IgM phenotype, reflecting defective class-switch recombination. + + ' cell_types: - preferred_term: B cell term: @@ -405,32 +332,21 @@ pathophysiology: causal_link_type: DIRECT evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - All patients had profound B-cell deficiency. - explanation: >- - Review confirms B-cell deficiency is a universal feature in EDA-ID2 patients. + snippet: All patients had profound B-cell deficiency. + explanation: Review confirms B-cell deficiency is a universal feature in EDA-ID2 patients. - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal - dysplasia - explanation: >- - Demonstrates hyper-IgM-like immunodeficiency as a manifestation of - defective B-cell class switching in IkBa-mutant patients. + snippet: a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal dysplasia + explanation: Demonstrates hyper-IgM-like immunodeficiency as a manifestation of defective B-cell class switching in IkBa-mutant patients. - name: Defective Lymph Node Development - description: > - Constitutive IkBa inhibition impairs both canonical and noncanonical NF-kB - signaling. The noncanonical pathway drives expression of chemokines and - adhesion molecules (CCL20, ICAM1, VCAM1) required for lymphorganogenesis. - In the S32I knock-in mouse model, lymph nodes and Peyer's patches are - completely absent. Defective stromal cell function contributes to persistent - immunodeficiency even after HSCT, as the non-hematopoietic compartment - retains the mutant IkBa. + description: 'Constitutive IkBa inhibition impairs both canonical and noncanonical NF-kB signaling. The noncanonical pathway drives expression of chemokines and adhesion molecules (CCL20, ICAM1, VCAM1) required for lymphorganogenesis. In the S32I knock-in mouse model, lymph nodes and Peyer''s patches are completely absent. Defective stromal cell function contributes to persistent immunodeficiency even after HSCT, as the non-hematopoietic compartment retains the mutant IkBa. + + ' biological_processes: - preferred_term: lymph node development term: @@ -441,35 +357,21 @@ pathophysiology: causal_link_type: DIRECT evidence: - reference: PMID:28629746 - reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." + reference_title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. supports: SUPPORT evidence_source: MODEL_ORGANISM - snippet: >- - the S32I mutant completely lacks lymph nodes (LNs), Peyer's patches, - marginal zone B cells and follicular dendritic cells, and fails to form - germinal centers, features typical of defective non-canonical NF-κB - signaling - explanation: >- - S32I knock-in mouse demonstrates that IkBa gain-of-function abolishes - lymph node organogenesis through impaired noncanonical NF-kB signaling. + snippet: the S32I mutant completely lacks lymph nodes (LNs), Peyer's patches, marginal zone B cells and follicular dendritic cells, and fails to form germinal centers, features typical of defective non-canonical NF-κB signaling + explanation: S32I knock-in mouse demonstrates that IkBa gain-of-function abolishes lymph node organogenesis through impaired noncanonical NF-kB signaling. - reference: PMID:28629746 - reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." + reference_title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. supports: SUPPORT evidence_source: MODEL_ORGANISM - snippet: >- - WT->S32I IκBα chimeras failed to form proper lymphoid organs and to - reconstitute immune function despite excellent donor cell engraftment, - paralleling the failure of HSCT to cure AD EDA-ID patients - explanation: >- - Demonstrates that defective stromal (non-hematopoietic) cell function - contributes to persistent immunodeficiency, explaining poor HSCT outcomes. + snippet: WT->S32I IκBα chimeras failed to form proper lymphoid organs and to reconstitute immune function despite excellent donor cell engraftment, paralleling the failure of HSCT to cure AD EDA-ID patients + explanation: Demonstrates that defective stromal (non-hematopoietic) cell function contributes to persistent immunodeficiency, explaining poor HSCT outcomes. - name: Ectodermal Dysplasia - description: > - NF-kB signaling through the ectodysplasin (EDA)/EDAR/NF-kB pathway is - essential for ectodermal appendage development. Constitutive IkBa inhibition - disrupts this pathway, leading to hypohidrosis from sweat gland hypoplasia, - sparse hair, and conical or absent teeth. Notably, some S36 missense variants - cause immunodeficiency without ectodermal dysplasia features. + description: 'NF-kB signaling through the ectodysplasin (EDA)/EDAR/NF-kB pathway is essential for ectodermal appendage development. Constitutive IkBa inhibition disrupts this pathway, leading to hypohidrosis from sweat gland hypoplasia, sparse hair, and conical or absent teeth. Notably, some S36 missense variants cause immunodeficiency without ectodermal dysplasia features. + + ' biological_processes: - preferred_term: ectodermal placode formation term: @@ -486,73 +388,59 @@ pathophysiology: causal_link_type: DIRECT evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Thirteen patients had developmental features of EDA, the severity and - nature of which differed between cases. - explanation: >- - EDA features are present in most but not all patients, with variable severity. + snippet: Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. + explanation: EDA features are present in most but not all patients, with variable severity. - reference: PMID:31683054 - reference_title: "A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia." + reference_title: A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - missense NFKBIA variants substituting serine 36 of IκBα, differ from the - rest of pathogenic GOF NFKBIA variants in that they cause combined - immunodeficiency, even in the absence of EDA - explanation: >- - Demonstrates genotype-phenotype correlation where S36 variants can cause - immunodeficiency without ectodermal dysplasia, indicating the EDA phenotype - is not obligate. + snippet: missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA + explanation: Demonstrates genotype-phenotype correlation where S36 variants can cause immunodeficiency without ectodermal dysplasia, indicating the EDA phenotype is not obligate. phenotypes: - category: Integumentary name: Hypohidrosis - description: > - Reduced or absent sweating due to sweat gland hypoplasia, a hallmark of - ectodermal dysplasia. Present in most but not all patients. + description: 'Reduced or absent sweating due to sweat gland hypoplasia, a hallmark of ectodermal dysplasia. Present in most but not all patients. + + ' phenotype_term: preferred_term: Hypohidrosis term: id: HP:0000966 label: Hypohidrosis evidence: - - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + - reference: PMID:28629746 + reference_title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Thirteen patients had developmental features of EDA, the severity and - nature of which differed between cases. - explanation: >- - Confirms ectodermal dysplasia features including hypohidrosis in the - majority of patients. + quote_role: BACKGROUND + snippet: Heterozygous mutations in the IκB family member IκBα cause autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID), characterized by sparse hair, conical teeth, reduced number of sweat glands, and susceptibility to severe infections. + explanation: Directly documents sparse hair and reduced sweat glands (anhidrotic/hypohidrotic ectodermal dysplasia) as defining clinical features of AD EDA-ID caused by heterozygous NFKBIA mutations. - category: Integumentary name: Sparse Hair - description: > - Sparse scalp hair and reduced body hair due to defective hair follicle - development as part of the ectodermal dysplasia spectrum. + description: 'Sparse scalp hair and reduced body hair due to defective hair follicle development as part of the ectodermal dysplasia spectrum. + + ' phenotype_term: preferred_term: Sparse scalp hair term: id: HP:0002209 label: Sparse scalp hair evidence: - - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + - reference: PMID:28629746 + reference_title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Thirteen patients had developmental features of EDA, the severity and - nature of which differed between cases. - explanation: >- - Confirms developmental ectodermal dysplasia manifestations including - sparse scalp hair across reported patients. + quote_role: BACKGROUND + snippet: Heterozygous mutations in the IκB family member IκBα cause autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID), characterized by sparse hair, conical teeth, reduced number of sweat glands, and susceptibility to severe infections. + explanation: Directly documents sparse hair and reduced sweat glands (anhidrotic/hypohidrotic ectodermal dysplasia) as defining clinical features of AD EDA-ID caused by heterozygous NFKBIA mutations. - category: Dental name: Conical Teeth - description: > - Small, conical-shaped teeth characteristic of ectodermal dysplasia. + description: 'Small, conical-shaped teeth characteristic of ectodermal dysplasia. + + ' phenotype_term: preferred_term: Small, conical teeth term: @@ -560,20 +448,16 @@ phenotypes: label: Small, conical teeth evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - several signs of ectodermal dysplasia became manifest and comprised - abnormal dentition (typical conical teeth) and periorbital wrinkling - explanation: >- - Direct clinical observation of conical teeth as part of ectodermal - dysplasia features in a patient with S32I IkBa mutation. + snippet: several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling + explanation: Direct clinical observation of conical teeth as part of ectodermal dysplasia features in a patient with S32I IkBa mutation. - category: Immunological name: Recurrent Infections - description: > - Severe recurrent pyogenic, mycobacterial, fungal, and viral infections - due to combined T-cell, B-cell, and innate immune dysfunction. + description: 'Severe recurrent pyogenic, mycobacterial, fungal, and viral infections due to combined T-cell, B-cell, and innate immune dysfunction. + + ' phenotype_term: preferred_term: Recurrent infections term: @@ -581,30 +465,22 @@ phenotypes: label: Recurrent infections evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - The patients had various pyogenic, mycobacterial, fungal, and viral - severe infections. - explanation: >- - Review confirms broad spectrum of severe infections as a universal feature. + snippet: The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. + explanation: Review confirms broad spectrum of severe infections as a universal feature. - reference: PMID:35005117 - reference_title: "A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response." + reference_title: A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - She presented recurrent fever, infectious pneumonia and chronic diarrhea - with EDA-ID. - explanation: >- - Case report documenting recurrent infections in a patient with an - N-terminal truncation NFKBIA mutation. + snippet: She presented recurrent fever, infectious pneumonia and chronic diarrhea with EDA-ID. + explanation: Case report documenting recurrent infections in a patient with an N-terminal truncation NFKBIA mutation. - category: Immunological name: Recurrent Mycobacterial Infections - description: > - Susceptibility to mycobacterial infections, including disseminated - nontuberculous mycobacterial disease, reflecting defective macrophage - activation and IL-12/IFN-gamma axis dysfunction. + description: 'Susceptibility to mycobacterial infections, including disseminated nontuberculous mycobacterial disease, reflecting defective macrophage activation and IL-12/IFN-gamma axis dysfunction. + + ' phenotype_term: preferred_term: Recurrent mycobacterial infections term: @@ -612,22 +488,16 @@ phenotypes: label: Recurrent mycobacterial infections evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - The patients had various pyogenic, mycobacterial, fungal, and viral - severe infections. - explanation: >- - Review confirms mycobacterial infections as part of the broad infection - susceptibility spectrum in EDA-ID2 patients. + snippet: The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. + explanation: Review confirms mycobacterial infections as part of the broad infection susceptibility spectrum in EDA-ID2 patients. - category: Immunological name: Lymphocytosis with Absent Memory T Cells - description: > - Characteristic immunological finding of marked blood lymphocytosis - composed almost entirely of naive T cells, with no detectable memory - T cells. Naive T cells fail to respond to CD3-TCR activation despite - their increased numbers. + description: 'Characteristic immunological finding of marked blood lymphocytosis composed almost entirely of naive T cells, with no detectable memory T cells. Naive T cells fail to respond to CD3-TCR activation despite their increased numbers. + + ' phenotype_term: preferred_term: Increased total lymphocyte count term: @@ -635,32 +505,22 @@ phenotypes: label: Increased total lymphocyte count evidence: - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Despite a marked blood lymphocytosis, there are no detectable memory - T cells in vivo, and naive T cells do not respond to CD3-TCR activation - in vitro. - explanation: >- - Demonstrates the paradoxical lymphocytosis with absent memory T cells - that is the hallmark T-cell abnormality of EDA-ID2. + snippet: Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. + explanation: Demonstrates the paradoxical lymphocytosis with absent memory T cells that is the hallmark T-cell abnormality of EDA-ID2. - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Specific immunological features, found in some, but not all patients, - included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional - α/β T cells, and a lack of circulating γ/δ T cells. - explanation: >- - Confirms lymphocytosis as a feature in some patients, along with - dysfunctional T cells and absent gamma/delta T cells. + snippet: Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. + explanation: Confirms lymphocytosis as a feature in some patients, along with dysfunctional T cells and absent gamma/delta T cells. - category: Immunological name: Decreased Circulating B Cell Count - description: > - Profound reduction in circulating B cells, a universal finding in patients - with IkBa gain-of-function mutations. + description: 'Profound reduction in circulating B cells, a universal finding in patients with IkBa gain-of-function mutations. + + ' phenotype_term: preferred_term: Decreased total B cell count term: @@ -668,18 +528,16 @@ phenotypes: label: Decreased total B cell count evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - All patients had profound B-cell deficiency. - explanation: >- - Universal feature confirmed across all reported EDA-ID2 patients. + snippet: All patients had profound B-cell deficiency. + explanation: Universal feature confirmed across all reported EDA-ID2 patients. - category: Immunological name: Agammaglobulinemia - description: > - Absent or severely reduced circulating immunoglobulins (IgG, IgA) due to - B-cell deficiency, often presenting with a hyper-IgM-like pattern. + description: 'Absent or severely reduced circulating immunoglobulins (IgG, IgA) due to B-cell deficiency, often presenting with a hyper-IgM-like pattern. + + ' phenotype_term: preferred_term: Agammaglobulinemia term: @@ -687,21 +545,16 @@ phenotypes: label: Agammaglobulinemia evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see - Table I) with a strongly increased serum IgM - explanation: >- - Direct clinical documentation of agammaglobulinemia with elevated IgM - in a patient with S32I mutation, consistent with defective class switching. + snippet: immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see Table I) with a strongly increased serum IgM + explanation: Direct clinical documentation of agammaglobulinemia with elevated IgM in a patient with S32I mutation, consistent with defective class switching. - category: Immunological name: Absent Peripheral Lymph Nodes - description: > - Absence of palpable peripheral lymph nodes despite active infections, - reflecting defective lymphorganogenesis from impaired noncanonical - NF-kB signaling in stromal cells. + description: 'Absence of palpable peripheral lymph nodes despite active infections, reflecting defective lymphorganogenesis from impaired noncanonical NF-kB signaling in stromal cells. + + ' phenotype_term: preferred_term: Absent peripheral lymph nodes in presence of infection term: @@ -709,22 +562,16 @@ phenotypes: label: Absent peripheral lymph nodes in presence of infection evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - Specific immunological features, found in some, but not all patients, - included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional - α/β T cells, and a lack of circulating γ/δ T cells. - explanation: >- - Absence of peripheral lymph nodes is a recognized feature in some - EDA-ID2 patients, consistent with defective lymphorganogenesis. + snippet: Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. + explanation: Absence of peripheral lymph nodes is a recognized feature in some EDA-ID2 patients, consistent with defective lymphorganogenesis. - category: Immunological name: Elevated IgM with Agammaglobulinemia - description: > - Hyper-IgM-like immunodeficiency pattern with strongly increased serum - IgM and absent or severely reduced IgG and IgA, reflecting defective - immunoglobulin class-switch recombination. + description: 'Hyper-IgM-like immunodeficiency pattern with strongly increased serum IgM and absent or severely reduced IgG and IgA, reflecting defective immunoglobulin class-switch recombination. + + ' phenotype_term: preferred_term: Increased circulating IgM level term: @@ -732,18 +579,16 @@ phenotypes: label: Increased circulating IgM level evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see - Table I) with a strongly increased serum IgM - explanation: >- - Direct documentation of the hyper-IgM pattern in an EDA-ID2 patient. + snippet: immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see Table I) with a strongly increased serum IgM + explanation: Direct documentation of the hyper-IgM pattern in an EDA-ID2 patient. - category: Integumentary name: Periorbital Wrinkles - description: > - Periorbital wrinkling as part of the ectodermal dysplasia phenotype. + description: 'Periorbital wrinkling as part of the ectodermal dysplasia phenotype. + + ' phenotype_term: preferred_term: Periorbital wrinkles term: @@ -751,25 +596,81 @@ phenotypes: label: Periorbital wrinkles evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling + explanation: Periorbital wrinkling observed alongside conical teeth as part of the ectodermal dysplasia features. +- category: Immunologic + name: Chronic Mucocutaneous Candidiasis + frequency: FREQUENT + description: Recurrent or persistent mucosal and cutaneous Candida infections responsive to antifungal therapy. + phenotype_term: + preferred_term: Chronic mucocutaneous candidiasis + term: + id: HP:0002728 + label: Chronic mucocutaneous candidiasis + evidence: + - reference: PMID:15337789 + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - several signs of ectodermal dysplasia became manifest and comprised - abnormal dentition (typical conical teeth) and periorbital wrinkling - explanation: >- - Periorbital wrinkling observed alongside conical teeth as part of the - ectodermal dysplasia features. + snippet: Except for intermittently recurrent mucosal candidiasis that responded to fluconazole, no subsequent serious infections were encountered during follow-up. + explanation: Documents recurrent mucosal candidiasis in a patient with NFKBIA gain-of-function mutation. +- category: Respiratory + name: Pneumocystis jirovecii Pneumonia + frequency: FREQUENT + description: Opportunistic pulmonary infection caused by Pneumocystis jirovecii (formerly Pneumocystis carinii) resulting from profound T-cell functional deficiency. + phenotype_term: + preferred_term: Pneumocystis jirovecii pneumonia + term: + id: HP:0020102 + label: Pneumocystis jirovecii pneumonia + evidence: + - reference: PMID:15337789 + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: In bronchoalveolar lavage fluid, Pneumocystis carinii was identified. + explanation: Directly confirms opportunistic Pneumocystis pneumonia in bronchoalveolar lavage fluid of an affected patient. +- category: Gastrointestinal + name: Chronic Diarrhea + frequency: FREQUENT + description: Persistent diarrhea associated with mucosal immune dysregulation and recurrent gastrointestinal infections. + phenotype_term: + preferred_term: Chronic diarrhea + term: + id: HP:0002028 + label: Chronic diarrhea + evidence: + - reference: PMID:35005117 + reference_title: A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response. + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: She presented recurrent fever, infectious pneumonia and chronic diarrhea with EDA-ID. + explanation: Documents chronic diarrhea as a core presenting feature in a patient with NFKBIA-related EDA-ID. +- category: Immunologic + name: Decreased Gamma-Delta T Cell Proportion + frequency: FREQUENT + description: Markedly reduced or absent circulating gamma-delta T lymphocytes in peripheral blood. + phenotype_term: + preferred_term: Absence of circulating gamma-delta T cells + term: + id: HP:0500271 + label: Decreased gamma-delta T cell proportion + evidence: + - reference: PMID:28597146 + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + quote_role: REVIEW_SYNTHESIS + snippet: Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. + explanation: Synthesizes cohort immunological findings showing lack of circulating gamma-delta T cells in patients with human IkBa gain of function. treatments: - name: Hematopoietic Stem Cell Transplantation - description: > - Allogeneic HSCT is the definitive treatment for the immunodeficiency - component, but outcomes are poor with high transplant-related mortality. - Five of eleven transplanted patients survived in a 2017 review, with - four requiring continued prophylaxis. Poor outcomes are partly attributed - to the non-hematopoietic (stromal) cell contribution to immunodeficiency, - as mutant IkBa in stromal cells impairs lymphorganogenesis even after - successful donor cell engraftment. + description: 'Allogeneic HSCT is the definitive treatment for the immunodeficiency component, but outcomes are poor with high transplant-related mortality. Five of eleven transplanted patients survived in a 2017 review, with four requiring continued prophylaxis. Poor outcomes are partly attributed to the non-hematopoietic (stromal) cell contribution to immunodeficiency, as mutant IkBa in stromal cells impairs lymphorganogenesis even after successful donor cell engraftment. + + ' therapeutic_modality: CELL_THERAPY treatment_term: preferred_term: hematopoietic stem cell transplantation @@ -778,53 +679,42 @@ treatments: label: Hematopoietic Cell Transplantation evidence: - reference: PMID:28597146 - reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency." - supports: SUPPORT - evidence_source: HUMAN_CLINICAL - snippet: >- - In the absence of hematopoietic stem cell transplantation (HSCT), this - condition cause death before the age of 1 year (one child). Two survivors - have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. - Five survived, four of whom have been on prophylaxis (3 to 21 years post - HSCT), whereas one has been well with no prophylaxis. - explanation: >- - Comprehensive outcomes data showing HSCT is necessary but carries high - mortality, with variable immune reconstitution in survivors. + reference_title: 'Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.' + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. + explanation: Comprehensive outcomes data showing HSCT is necessary but carries high mortality, with variable immune reconstitution in survivors. - reference: PMID:28629746 - reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency." + reference_title: Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - The outcome of hematopoietic stem cell transplantation is poor in patients - with AD EDA-ID despite achievement of chimerism. - explanation: >- - Demonstrates that poor HSCT outcomes persist despite chimerism, due to - stromal cell contribution from non-hematopoietic compartment. + snippet: The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. + explanation: Demonstrates that poor HSCT outcomes persist despite chimerism, due to stromal cell contribution from non-hematopoietic compartment. - name: Antimicrobial Prophylaxis - description: > - Prophylactic antimicrobials are essential for patients who do not undergo - HSCT or who have incomplete immune reconstitution post-transplant. - Includes antibacterial, antifungal, and Pneumocystis prophylaxis. + description: 'Prophylactic antimicrobials are essential for patients who do not undergo HSCT or who have incomplete immune reconstitution post-transplant. Includes antibacterial, antifungal, and Pneumocystis prophylaxis. + + ' treatment_term: preferred_term: antimicrobial agent therapy term: id: NCIT:C15986 label: Pharmacotherapy + therapeutic_agent: + - preferred_term: co-trimoxazole + term: + id: CHEBI:3770 + label: co-trimoxazole evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - From the second infection onwards, Ig substitution was initiated together - with cotrimoxazole as P. carinii prophylaxis. - explanation: >- - Demonstrates clinical use of cotrimoxazole as Pneumocystis carinii - antimicrobial prophylaxis in an EDA-ID2 patient. + snippet: From the second infection onwards, Ig substitution was initiated together with cotrimoxazole as P. carinii prophylaxis. + explanation: Demonstrates clinical use of cotrimoxazole as Pneumocystis carinii antimicrobial prophylaxis in an EDA-ID2 patient. - name: Immunoglobulin Replacement Therapy - description: > - Intravenous or subcutaneous immunoglobulin replacement for patients - with agammaglobulinemia or hypogammaglobulinemia. + description: 'Intravenous or subcutaneous immunoglobulin replacement for patients with agammaglobulinemia or hypogammaglobulinemia. + + ' treatment_term: preferred_term: intravenous immunoglobulin therapy term: @@ -832,22 +722,14 @@ treatments: label: Intravenous Immunoglobulin Therapy evidence: - reference: PMID:15337789 - reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes." + reference_title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - From the second infection onwards, Ig substitution was initiated together - with cotrimoxazole as P. carinii prophylaxis. - explanation: >- - Demonstrates clinical use of immunoglobulin substitution and antimicrobial - prophylaxis in managing an EDA-ID2 patient. + snippet: From the second infection onwards, Ig substitution was initiated together with cotrimoxazole as P. carinii prophylaxis. + explanation: Demonstrates clinical use of immunoglobulin substitution and antimicrobial prophylaxis in managing an EDA-ID2 patient. diagnosis: - name: NFKBIA Molecular Genetic Testing - description: >- - Targeted sequence analysis or exome/genome sequencing of NFKBIA to identify - heterozygous gain-of-function variants affecting the DSGxxS degron motif - (Ser32, Ser36, or adjacent residues) or producing N-terminally truncated - IkBa proteins resistant to signal-induced phosphorylation and degradation. + description: Targeted sequence analysis or exome/genome sequencing of NFKBIA to identify heterozygous gain-of-function variants affecting the DSGxxS degron motif (Ser32, Ser36, or adjacent residues) or producing N-terminally truncated IkBa proteins resistant to signal-induced phosphorylation and degradation. diagnosis_term: preferred_term: molecular genetic testing term: @@ -855,24 +737,14 @@ diagnosis: label: Genetic Testing evidence: - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. supports: SUPPORT evidence_source: HUMAN_CLINICAL - snippet: >- - an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous - missense mutation at serine 32 of IkappaBalpha - explanation: >- - Establishes identification of heterozygous NFKBIA (IkappaBalpha) mutations - at serine 32 as the molecular basis for diagnosing autosomal dominant - EDA-ID. + snippet: an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha + explanation: Establishes identification of heterozygous NFKBIA (IkappaBalpha) mutations at serine 32 as the molecular basis for diagnosing autosomal dominant EDA-ID. differential_diagnoses: - name: X-Linked Ectodermal Dysplasia and Immunodeficiency 1 - description: >- - Caused by hemizygous hypomorphic mutations in IKBKG (NEMO), presenting with - overlapping anhidrotic ectodermal dysplasia and pyogenic/mycobacterial - susceptibility, but distinguished by X-linked inheritance and the absence - of the severe naive T-cell lymphocytosis and memory T-cell deficiency - characteristic of NFKBIA gain-of-function disease. + description: Caused by hemizygous hypomorphic mutations in IKBKG (NEMO), presenting with overlapping anhidrotic ectodermal dysplasia and pyogenic/mycobacterial susceptibility, but distinguished by X-linked inheritance and the absence of the severe naive T-cell lymphocytosis and memory T-cell deficiency characteristic of NFKBIA gain-of-function disease. distinguishing_features: - X-linked recessive inheritance via IKBKG (NEMO) rather than autosomal dominant NFKBIA gain-of-function - Preserved memory T-cell development and in vitro TCR responsiveness compared to the severe naive T-cell block in EDA-ID2 @@ -883,15 +755,8 @@ differential_diagnoses: label: IKBKG-related immunodeficiency with or without ectodermal dysplasia evidence: - reference: PMID:14523047 - reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency." - supports: SUPPORT - evidence_source: HUMAN_CLINICAL - snippet: >- - AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell - immunodeficiency. Despite a marked blood lymphocytosis, there are no - detectable memory T cells in vivo, and naive T cells do not respond to - CD3-TCR activation in vitro. - explanation: >- - Distinguishes autosomal dominant EDA-ID2 from X-linked EDA-ID1 by the - unique severe T-cell immunodeficiency with blood lymphocytosis, absent - memory T cells, and impaired CD3-TCR activation. + reference_title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. + supports: SUPPORT + evidence_source: HUMAN_CLINICAL + snippet: AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. + explanation: Distinguishes autosomal dominant EDA-ID2 from X-linked EDA-ID1 by the unique severe T-cell immunodeficiency with blood lymphocytosis, absent memory T cells, and impaired CD3-TCR activation. From 4a6bf3bbefa4724e54776bf6aec605ca54f9d49c Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Sun, 18 Oct 2026 01:45:18 -0700 Subject: [PATCH 4/6] Address review feedback for Ectodermal_Dysplasia_and_Immunodeficiency_2 --- cache/go/terms.csv | 1 + ...ysplasia-and-immunodeficiency-2-review.yaml | 18 ++++++++---------- ...ermal_Dysplasia_and_Immunodeficiency_2.yaml | 16 ++++++---------- 3 files changed, 15 insertions(+), 20 deletions(-) diff --git a/cache/go/terms.csv b/cache/go/terms.csv index 51662271285..4d8e061a1f5 100644 --- a/cache/go/terms.csv +++ b/cache/go/terms.csv @@ -3522,6 +3522,7 @@ GO:0051017,actin filament bundle assembly,2026-08-24T00:33:25.589040 GO:0051018,protein kinase A binding,2026-09-03T20:55:09.389098 GO:0051028,mRNA transport,2026-08-19T09:37:38.104111 GO:0051056,regulation of small GTPase mediated signal transduction,2026-06-05T14:39:52.366759 +GO:0051059,NF-kappaB binding,2026-10-18T01:01:08.994701 GO:0051082,obsolete unfolded protein binding,2026-08-23T03:00:45.378722 GO:0051087,protein-folding chaperone binding,2026-07-22T12:56:33.809754 GO:0051092,obsolete positive regulation of NF-kappaB transcription factor activity,2026-03-17T19:24:47.720819 diff --git a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml index 617c560a7d0..d92c527af2e 100644 --- a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml +++ b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml @@ -20,17 +20,15 @@ events: - type: REVIEW outcome: changed sections: + - classifications + - prevalence + - progression - pathophysiology - phenotypes - genetic + - diagnosis + - differential_diagnoses - treatments - summary: Deepen Ectodermal Dysplasia and Immunodeficiency 2 with GO:0140297 transcription factor binding grounding, AD EDA-ID-specific - PMID:28629746 phenotype evidence, four additional phenotypes, structured gene_disease_validity, and CHEBI:3770 therapeutic_agent. - details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0140297 (DNA-binding transcription - factor binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream pathophysiology nodes to clinical - phenotypes including Severe Combined Immunodeficiency, Mycobacterial Infections, Chronic Diarrhea, and Impaired Polysaccharide - Antibody Response, replaced generic ectodermal dysplasia snippets with AD EDA-ID-specific PMID:28629746 evidence, populated - gene_disease_validity: DEFINITIVE on NFKBIA and therapeutic_agent CHEBI:3770 on Antimicrobial Prophylaxis, and added classifications, - prevalence, progression, diagnosis, and differential_diagnoses sections. - - ' + summary: 'Deepen Ectodermal Dysplasia and Immunodeficiency 2 with GO:0051059 (NF-kappaB binding) grounding, AD EDA-ID-specific PMID:28629746 phenotype evidence, four additional phenotypes, structured gene_disease_validity, and CHEBI:3770 therapeutic_agent.' + details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0051059 (NF-kappaB binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream pathophysiology nodes to clinical phenotypes including Chronic Mucocutaneous Candidiasis (HP:0002728), Pneumocystis jirovecii Pneumonia (HP:0020102), Chronic Diarrhea (HP:0002028), and Decreased Gamma-Delta T Cell Proportion (HP:0500255), replaced generic ectodermal dysplasia snippets with AD EDA-ID-specific PMID:28629746 evidence, populated gene_disease_validity: DEFINITIVE on NFKBIA and therapeutic_agent CHEBI:3770 on Antimicrobial Prophylaxis, and added classifications, prevalence, progression, diagnosis, and differential_diagnoses sections. +' diff --git a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml index c22d954a69f..241a9e358e0 100644 --- a/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml +++ b/kb/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2.yaml @@ -216,10 +216,10 @@ pathophysiology: snippet: All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. explanation: Review confirming that all reported mutations share the same gain-of-function mechanism of preventing IkBa phosphorylation. molecular_functions: - - preferred_term: DNA-binding transcription factor binding + - preferred_term: NF-kappaB binding term: - id: GO:0140297 - label: DNA-binding transcription factor binding + id: GO:0051059 + label: NF-kappaB binding modifier: INCREASED - name: Impaired T Cell Development and Function description: 'NF-kB signaling is essential for T-cell development, activation, and survival. Constitutive IkBa-mediated NF-kB inhibition results in a unique T-cell immunodeficiency characterized by lymphocytosis with absence of memory T cells and failure of naive T cells to respond to TCR stimulation. @@ -601,9 +601,8 @@ phenotypes: evidence_source: HUMAN_CLINICAL snippet: several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling explanation: Periorbital wrinkling observed alongside conical teeth as part of the ectodermal dysplasia features. -- category: Immunologic +- category: Immunological name: Chronic Mucocutaneous Candidiasis - frequency: FREQUENT description: Recurrent or persistent mucosal and cutaneous Candida infections responsive to antifungal therapy. phenotype_term: preferred_term: Chronic mucocutaneous candidiasis @@ -617,9 +616,8 @@ phenotypes: evidence_source: HUMAN_CLINICAL snippet: Except for intermittently recurrent mucosal candidiasis that responded to fluconazole, no subsequent serious infections were encountered during follow-up. explanation: Documents recurrent mucosal candidiasis in a patient with NFKBIA gain-of-function mutation. -- category: Respiratory +- category: Immunological name: Pneumocystis jirovecii Pneumonia - frequency: FREQUENT description: Opportunistic pulmonary infection caused by Pneumocystis jirovecii (formerly Pneumocystis carinii) resulting from profound T-cell functional deficiency. phenotype_term: preferred_term: Pneumocystis jirovecii pneumonia @@ -635,7 +633,6 @@ phenotypes: explanation: Directly confirms opportunistic Pneumocystis pneumonia in bronchoalveolar lavage fluid of an affected patient. - category: Gastrointestinal name: Chronic Diarrhea - frequency: FREQUENT description: Persistent diarrhea associated with mucosal immune dysregulation and recurrent gastrointestinal infections. phenotype_term: preferred_term: Chronic diarrhea @@ -649,9 +646,8 @@ phenotypes: evidence_source: HUMAN_CLINICAL snippet: She presented recurrent fever, infectious pneumonia and chronic diarrhea with EDA-ID. explanation: Documents chronic diarrhea as a core presenting feature in a patient with NFKBIA-related EDA-ID. -- category: Immunologic +- category: Immunological name: Decreased Gamma-Delta T Cell Proportion - frequency: FREQUENT description: Markedly reduced or absent circulating gamma-delta T lymphocytes in peripheral blood. phenotype_term: preferred_term: Absence of circulating gamma-delta T cells From 1db2fb7c575637969a1d49fb3f059e49f8a27387 Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Sun, 18 Oct 2026 03:05:31 -0700 Subject: [PATCH 5/6] Fix history CURIE and commit GO:0051059 enum cache row for EDAID2 --- cache/enums/molecularfunctionterm_305077eac108.csv | 1 + cache/go/terms.csv | 1 - ...ity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml | 3 +-- 3 files changed, 2 insertions(+), 3 deletions(-) diff --git a/cache/enums/molecularfunctionterm_305077eac108.csv b/cache/enums/molecularfunctionterm_305077eac108.csv index a8a2772afb0..6cb16162387 100644 --- a/cache/enums/molecularfunctionterm_305077eac108.csv +++ b/cache/enums/molecularfunctionterm_305077eac108.csv @@ -947,6 +947,7 @@ GO:0050839 GO:0050840 GO:0051015 GO:0051018 +GO:0051059 GO:0051087 GO:0051117 GO:0051371 diff --git a/cache/go/terms.csv b/cache/go/terms.csv index 9dfc099e202..4d8e061a1f5 100644 --- a/cache/go/terms.csv +++ b/cache/go/terms.csv @@ -1271,7 +1271,6 @@ GO:0006979,response to oxidative stress,2026-03-17T19:23:56.867567 GO:0006986,response to unfolded protein,2026-03-17T19:32:55.080174 GO:0006997,nucleus organization,2026-09-25T14:21:36.810819 GO:0006998,nuclear envelope organization,2026-03-17T19:45:49.768367 -GO:0006999,nuclear pore organization,2026-10-17T01:02:20.515718 GO:0007000,nucleolus organization,2026-06-12T06:09:47.095326 GO:0007004,telomere maintenance via telomerase,2026-03-17T19:36:35.237201 GO:0007005,mitochondrion organization,2026-03-17T19:24:14.202602 diff --git a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml index d92c527af2e..5c3a765b54f 100644 --- a/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml +++ b/history/disorders/Ectodermal_Dysplasia_and_Immunodeficiency_2/2026-10-17T17-00-00Z-antigravity-ectodermal-dysplasia-and-immunodeficiency-2-review.yaml @@ -30,5 +30,4 @@ events: - differential_diagnoses - treatments summary: 'Deepen Ectodermal Dysplasia and Immunodeficiency 2 with GO:0051059 (NF-kappaB binding) grounding, AD EDA-ID-specific PMID:28629746 phenotype evidence, four additional phenotypes, structured gene_disease_validity, and CHEBI:3770 therapeutic_agent.' - details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0051059 (NF-kappaB binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream pathophysiology nodes to clinical phenotypes including Chronic Mucocutaneous Candidiasis (HP:0002728), Pneumocystis jirovecii Pneumonia (HP:0020102), Chronic Diarrhea (HP:0002028), and Decreased Gamma-Delta T Cell Proportion (HP:0500255), replaced generic ectodermal dysplasia snippets with AD EDA-ID-specific PMID:28629746 evidence, populated gene_disease_validity: DEFINITIVE on NFKBIA and therapeutic_agent CHEBI:3770 on Antimicrobial Prophylaxis, and added classifications, prevalence, progression, diagnosis, and differential_diagnoses sections. -' + details: 'Wired NFKBIA into the IkBa Gain-of-Function pathophysiological trigger node with GO:0051059 (NF-kappaB binding, INCREASED) and modifier DECREASED on GO:0007249, connected downstream pathophysiology nodes to clinical phenotypes including Chronic Mucocutaneous Candidiasis (HP:0002728), Pneumocystis jirovecii Pneumonia (HP:0020102), Chronic Diarrhea (HP:0002028), and Decreased Gamma-Delta T Cell Proportion (HP:0500271), replaced generic ectodermal dysplasia snippets with AD EDA-ID-specific PMID:28629746 evidence, populated gene_disease_validity: DEFINITIVE on NFKBIA and therapeutic_agent CHEBI:3770 on Antimicrobial Prophylaxis, and added classifications, prevalence, progression, diagnosis, and differential_diagnoses sections.' From cd4b42edc41483a631aa35ddf968e7d328b1af0f Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Sun, 18 Oct 2026 03:36:33 -0700 Subject: [PATCH 6/6] Restore GO:0006999 in cache/go/terms.csv and re-cache GO:0051059 --- cache/go/terms.csv | 3 ++- 1 file changed, 2 insertions(+), 1 deletion(-) diff --git a/cache/go/terms.csv b/cache/go/terms.csv index 4d8e061a1f5..68d01954440 100644 --- a/cache/go/terms.csv +++ b/cache/go/terms.csv @@ -1271,6 +1271,7 @@ GO:0006979,response to oxidative stress,2026-03-17T19:23:56.867567 GO:0006986,response to unfolded protein,2026-03-17T19:32:55.080174 GO:0006997,nucleus organization,2026-09-25T14:21:36.810819 GO:0006998,nuclear envelope organization,2026-03-17T19:45:49.768367 +GO:0006999,nuclear pore organization,2026-10-17T01:02:20.515718 GO:0007000,nucleolus organization,2026-06-12T06:09:47.095326 GO:0007004,telomere maintenance via telomerase,2026-03-17T19:36:35.237201 GO:0007005,mitochondrion organization,2026-03-17T19:24:14.202602 @@ -3522,7 +3523,7 @@ GO:0051017,actin filament bundle assembly,2026-08-24T00:33:25.589040 GO:0051018,protein kinase A binding,2026-09-03T20:55:09.389098 GO:0051028,mRNA transport,2026-08-19T09:37:38.104111 GO:0051056,regulation of small GTPase mediated signal transduction,2026-06-05T14:39:52.366759 -GO:0051059,NF-kappaB binding,2026-10-18T01:01:08.994701 +GO:0051059,NF-kappaB binding,2026-10-18T03:35:39.437686 GO:0051082,obsolete unfolded protein binding,2026-08-23T03:00:45.378722 GO:0051087,protein-folding chaperone binding,2026-07-22T12:56:33.809754 GO:0051092,obsolete positive regulation of NF-kappaB transcription factor activity,2026-03-17T19:24:47.720819