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Autoinflammatory disorders v2.34 RELA Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RELA.
Tag Q2_25_ NHS_review was removed from gene: RELA.
Autoinflammatory disorders v2.34 RELA Achchuthan Shanmugasundram reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.33 RELA Achchuthan Shanmugasundram Source NHS GMS was added to RELA.
Source Expert Review Green was added to RELA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient-derived ITCH-deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska commented on gene: ITCH: Comment on list classification:
There are at least 14 patients from 5 unrelated families with biallelic variants in ITCH. ITCH deficiency may result in multi-systemic immune dysregulation (present in 9/14 reported patients), dysmorphic features (14/14), developmental delay (14/14), relative macrocephaly (13/14), chronic lung disease (13/14), hepatomegaly/splenomegaly (10/14), and hypotonia (8/14). Based on available evidence, ITCH should be rated Green for autoinflammatory disorders.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR), flux through fatty acid oxidation, and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR), flux through fatty acid oxidation, and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Autoinflammatory disorders v2.26 RELA Arina Puzriakova Publications for gene: RELA were set to PMID: 36926348; PMID: 32969189; PMID: 35412596; PMID: 28600438
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Tag Q2_23_NHS_review was removed from gene: RELA.
Tag Q2_25_ NHS_review tag was added to gene: RELA.
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: RELA.
Tag Q2_23_NHS_review tag was added to gene: RELA.
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Classified gene: RELA as Amber List (moderate evidence)
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

At least 7 unrelated cases identified in literature with monoallelic RELA variants and Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287 which is characterised predominantly by intermittent fevers and chronic mucocutaneous ulceration although clinical presentation can be variable.
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Gene: rela has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram changed review comment from: PMID:34363755 reported the identification of homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620880).; to: PMID:34363755 reported the identification of three different homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620880).
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Autoinflammatory disorders v2.21 RELA Arina Puzriakova Phenotypes for gene: RELA were changed from Autoinflammatory disease, familial, behcet-like 3 to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
Autoinflammatory disorders v2.20 POMP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 4 unrelated cases with neonatal onset inflammatory disease and heterozygous LOF variants in the POMP gene (PMID: 26524591; 29805043; 38111302)
Autoinflammatory disorders v2.16 IKBKG Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Variants in the IKBKG gene (also known as NEMO) can be linked to a autoinflammatory disorder characterised by the onset of systemic autoinflammation in the first months of life. Clinical manifestations are variable but include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. At least 9 unrelated cases have been reported, including two females (PMID: 31874111; 35120036; 35289316; 39264518).
Autoinflammatory disorders v2.11 ELF4 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous variants and autoinflammatory disorder, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

The 'skewed X-inactivation' tag has also been added.; to: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder in PMID:39976696, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

The 'Skewed X-inactivation' tag has also been added as skewed X chromosome inactivation patterns were observed in all three female patients in the same publication.
Autoinflammatory disorders v2.11 ELF4 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous variants and autoinflammatory disorder, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

The 'skewed X-inactivation' tag has also been added.
Autoinflammatory disorders v2.10 ELF4 Achchuthan Shanmugasundram edited their review of gene: ELF4: Added comment: PMID:34326534 - Two variants identified in three unrelated males with autoinflammatory disease characterised by fever, oral ulcers and mucosal inflammation. Supported by functional studies and mouse model.

PMID:35266071 - Paediatric male patient identified with a hemizygous variant and was suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer, constipation, and arthritis. Supported by functional studies and mouse model.

PMID:36823308 - Five more male patients presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anaemia, or systemic lupus erythematosus.

PMID:38231408 - An international cohort of fourteen patients exhibiting a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anaemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum.

PMID:38773005 - A 11-year-old boy presented with a Behcet's-like phenotype including elevated inflammatory indicators, ileocecal ulcers and inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-alpha blocker. Supporting functional studies available.

PMID:39563044 - Two male patients presented with recurrent oral ulcers and abdominal pain and had significant increase in inflammatory markers, multiple intestinal ulcers, and both patients developed intestinal fistulas.

PMID:39976696 - Three unrelated paediatric female patients, who are all heterozygous for ELF4 variants. Similar to reported male patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhoea with colonoscopy showing ulcers in the colon. Skewed X chromosome inactivation patterns were observed in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.; Changed publications to: 34326534, 35266071, 36823308, 38231408, 38773005, 39563044, 39976696
Autoinflammatory disorders v2.6 ALPK1 Achchuthan Shanmugasundram changed review comment from: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.; to: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

Gain-of-function missense variants in ALPK1 were reported to cause ROSAH in PMID:35868845.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.
Autoinflammatory disorders v2.6 ALPK1 Achchuthan Shanmugasundram commented on gene: ALPK1: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.
Autoinflammatory disorders v2.5 RELA Dorota Rowczenio gene: RELA was added
gene: RELA was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature,Research
Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RELA were set to PMID: 36926348; PMID: 32969189; PMID: 35412596; PMID: 28600438
Phenotypes for gene: RELA were set to Autoinflammatory disease, familial, behcet-like 3
Review for gene: RELA was set to GREEN
Added comment: Sources: Expert list, Expert Review, Literature, Research
Autoinflammatory disorders v2.4 COPA Arina Puzriakova gene: COPA was added
gene: COPA was added to Autoinflammatory disorders. Sources: Literature
Q2_25_ promote_green tags were added to gene: COPA.
Mode of inheritance for gene: COPA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COPA were set to 25894502; 31455335; 38175705
Phenotypes for gene: COPA were set to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414; COPA syndrome
Review for gene: COPA was set to GREEN
Added comment: Heterozygous variants in the COPA gene cause an autoinflammatory disorder that affects multiple organ systems. Affected individuals usually present in the first decade of life with variable features including interstitial lung disease with or without pulmonary hemorrhage, inflammatory arthritis, recurrent infections, and renal disease. Laboratory studies show evidence of systemic inflammation.

At least 9 unrelated families with more than 20 affected individuals have been reported in the literature (PMIDs: PMID: 25894502; 31455335; 38175705).

Variant hotspots include the WD40 domain and the C-terminal domain of the COPA protein.
Sources: Literature
Autoinflammatory disorders v2.3 OGFRL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. Rating Amber, awaiting further cases. To date, a single publication (PMID: 38699440) has reported two unrelated cherubism families with homozygous variants in this gene.
Autoinflammatory disorders v2.1 OGFRL1 Hannah Knight gene: OGFRL1 was added
gene: OGFRL1 was added to Autoinflammatory disorders. Sources: Literature
Mode of inheritance for gene: OGFRL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGFRL1 were set to PMID: 38699440
Phenotypes for gene: OGFRL1 were set to Cherubism
Review for gene: OGFRL1 was set to AMBER
Added comment: PMID: 38699440 (2024) identified two different homozygous LOF mutations in two unrelated families with cherubism. Functional work carried out, but inconclusive - mouse model did not recapitulate human cherubism
Sources: Literature
Autoinflammatory disorders v1.12 ADA Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with partial ADA deficiency or severe combined immunodeficiency (SCID) due to ADA deficiency with multiple unrelated cases reported.

Despite ADA null mice displaying severe pulmonary inflammation, could not find evidence of an autoinflammatory component observed in patients and therefore rating as Red on this panel
Autoinflammatory disorders v1.7 SEC23B Arina Puzriakova changed review comment from: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with congenital dyserythropoietic anemia (CDA) type II with multiple unrelated cases reported. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs. Could not find evidence of an autoinflammatory component of this disorder and therefore rating as red on this panel.; to: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with congenital dyserythropoietic anemia (CDA) type II with multiple unrelated cases reported. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs. Could not find strong evidence of an autoinflammatory component of this disorder and therefore rating as red on this panel.
Autoinflammatory disorders v1.7 SEC23B Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with congenital dyserythropoietic anemia (CDA) type II with multiple unrelated cases reported. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs. Could not find evidence of an autoinflammatory component of this disorder and therefore rating as red on this panel.
Autoinflammatory disorders v1.5 PRF1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with
Hemophagocytic Lymphohistiocytosis (HLH) with multiple unrelated cases reported. This is a hyperinflammatory disorder which leads to to impaired function of cytotoxic T cells and NK cells, consistent with a defect in cellular cytotoxicity. Acquired HLH can be caused by autoinflammatory and autoimmune diseases; however, familial HLH caused by biallelic variants in this gene do not necessarily cause autoinflammation.

For this reason, rating this gene:disease association as amber on this panel. Cases should be picked up via the 'R15 Primary immunodeficiency or monogenic inflammatory bowel disease' panel, where it is already green.
Autoinflammatory disorders v0.4 Arina Puzriakova List of related panels changed from to R413