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13 Mar 2026	Primary immunodeficiency or monogenic inflammatory bowel disease v8.84	RNU4ATAC	Ida Ertmanska changed review comment from: PMID: 26522830 Merico et al., 2015 6 cases with Roifman syndrome from 4 unrelated families (English, Italian, Lebanese, Albanian). All 6 had history of repeat infections. PMID: 28623346 Bogaert et al., 2017 Report of two siblings that presented with a phenotype resembling early-onset common variable immunodeficiency - extra-immunological characteristics were not apparent at that time. Additional features were diagnosed later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed c.13 C > T and c.116 A > T RNU4ATAC variants, which is consistent with diagnosis of Roifman syndrome. PMID: 29391254 Heremans et al., 2018 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC. All patients have a common phenotype of moderate psychomotor delay and autism spectrum disorder, retinal dystrophy with hypovascularization, severe growth retardation, spondyloepiphysial dysplasia with irregularly shaped vertebral bodies with platyspondyly and flattened proximal femoral epiphyses, pruritic ichthyosis-like skin rash, brachydactyly, hyperlaxity, hypotonia, and hepatosplenomegaly. All 3 patients have hypogammaglobulinemia and B-cell lymphopenia, and they experience recurrent viral infections, necessitating immunoglobulin substitution therapy. P2 had mucocutaneous Herpes simplex infection, and P3 presented a pneumococcal sepsis on discontinuation of therapy. Study showed abnormal differentiation of B cells and megakaryocytes in the patients. PMID: 33059947 Hagiwara et al., 2020 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at age one, resulting in severe psychomotor disabilities. Genetic analysis revealed comp het variants in RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity, and little response to vaccinations. RNU4ATAC is associated with multiple AR conditions in OMIM: Lowry-Wood syndrome, MIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, MIM:210710; Roifman syndrome, OMIM:616651. Only Roifman syndrome features immunodeficiency.; to: PMID: 26522830 Merico et al., 2015 6 cases with Roifman syndrome from 4 unrelated families (English, Italian, Lebanese, Albanian). All 6 had history of repeat infections. PMID: 28623346 Bogaert et al., 2017 Report of two siblings that presented with a phenotype resembling early-onset common variable immunodeficiency - extra-immunological characteristics were not apparent at that time. Additional features were diagnosed later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed c.13 C > T and c.116 A > T RNU4ATAC variants, which is consistent with diagnosis of Roifman syndrome. PMID: 29391254 Heremans et al., 2018 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC. All patients have a common phenotype of moderate psychomotor delay and autism spectrum disorder, retinal dystrophy with hypovascularization, severe growth retardation, spondyloepiphysial dysplasia with irregularly shaped vertebral bodies with platyspondyly and flattened proximal femoral epiphyses, pruritic ichthyosis-like skin rash, brachydactyly, hyperlaxity, hypotonia, and hepatosplenomegaly. All 3 patients have hypogammaglobulinemia and B-cell lymphopenia, and they experience recurrent viral infections, necessitating immunoglobulin substitution therapy. P2 had mucocutaneous Herpes simplex infection, and P3 presented a pneumococcal sepsis on discontinuation of therapy. Study showed abnormal differentiation of B cells and megakaryocytes in the patients. PMID: 33059947 Hagiwara et al., 2020 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at age one, resulting in severe psychomotor disabilities. Genetic analysis revealed comp het variants in RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity, and little response to vaccinations. MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567 identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation. RNU4ATAC is associated with multiple AR conditions in OMIM: Lowry-Wood syndrome, MIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, MIM:210710; Roifman syndrome, OMIM:616651. Only Roifman syndrome features immunodeficiency.
05 Nov 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.73	AIRE	Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients). AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. BIALLELIC: PMID: 25926518 Borgault et al., 2015 Report of 5 molecularly confirmed cases with APS1 (age range: 19 months–44 years). P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. No immunodeficiency noted. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia & Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients). AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
05 Nov 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.73	AIRE	Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients). AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
05 Nov 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.73	AIRE	Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
05 Nov 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.73	AIRE	Ida Ertmanska changed review comment from: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
05 Nov 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.73	AIRE	Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative.; to: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
29 Oct 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.66	C2	Arina Puzriakova Phenotypes for gene: C2 were changed from Complement Component C2 Deficiency; C2 deficiency, 217000; Immunodeficiency due to C1, C4, or C2 component complement deficiency; Lupus; SLE, infections with encapsulated organisms, atherosclerosis; Complement Deficiencies to C2 deficiency, OMIM:217000; complement component 2 deficiency, MONDO:0009006
24 Jul 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v8.19	DPP9	Hannah Knight gene: DPP9 was added gene: DPP9 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DPP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPP9 were set to PMID: 36112693 Phenotypes for gene: DPP9 were set to Hatipoglu immunodeficiency syndrome Review for gene: DPP9 was set to GREEN Added comment: PMID: 36112693 reported four patients from three unrelated families with biallelic DPP9 variants causing Hatipoglu immunodeficiency syndrome: - A 6-year-old boy, born of unrelated parents of Ashkenazi Jewish descent, with compound heterozygous variants (p.S214X and p.G167S) - A 14-year-old boy, born of consanguineous Turkish parents, with a homozygous variant (p.Q851X) - Two male patients from a consanguineous Bedouin family in Israel, with a homozygous variant (p.R111X) Sources: Literature
16 Apr 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v7.27	C2	Sarah Leigh reviewed gene: C2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: C2 deficiency, OMIM:217000, complement component 2 deficiency, MONDO:0009006; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
07 Apr 2025	Primary immunodeficiency or monogenic inflammatory bowel disease v7.26	GCC2	Boaz Palterer gene: GCC2 was added gene: GCC2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: GCC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GCC2 were set to 39813120 Phenotypes for gene: GCC2 were set to NK cell deficiency; recurrent viral infections; immunodeficiency Penetrance for gene: GCC2 were set to unknown Review for gene: GCC2 was set to RED Added comment: Pedroza et al. described 2 patients in two separate kindreds with compound heterozygous GCC2 mutations presenting in childhood with recurrent viral infections, normal NK cell numbers but reduced NK cell function. During NK cell activation, lytic granules (LGs) converge to the MTOC, enabling precision in cytotoxicity. Pedroza et al. demonstrate that GCC2 maintains convergence via tethering LGs to the Golgi. Absence of GCC2 leads to LG dispersion, non-directed degranulation, and bystander killing, and biallelic missense variants result in human NK cell deficiency. Sources: Literature
10 Nov 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v7.15	TNFSF9	Boaz Palterer gene: TNFSF9 was added gene: TNFSF9 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: TNFSF9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFSF9 were set to 35657354 Phenotypes for gene: TNFSF9 were set to EBV lymphoproliferation; smooth muscle tumors Penetrance for gene: TNFSF9 were set to unknown Review for gene: TNFSF9 was set to RED Added comment: Fournier et al. described one patient with DiGeorge syndrome with a unique susceptibility to EBV with broad EBV infection and smooth muscle tumors. He was found to have a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. They show that CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Sources: Literature
08 Nov 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v7.14	IL27RA	Achchuthan Shanmugasundram changed review comment from: PMID:38509369 reported three children from two families with severe acute primary Epstein-Barr virus infection. One family was reported with a homozygous p.Gln96Ter variant and the other family was reported with compound heterozygous variants - an-inframe deletion of (p.Gln381_Ala395del) and a missense variant p.Arg446Gly. p.Arg446Gly was identified in homozygous state in 15 individuals from FinnGen database, which contains >400,000 individuals. Two of these individuals had hospital diagnoses of EBV infectious mononucleosis (IM). There is extensive ex vivo and in vitro data available, including mice model. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:38509369 reported three children from two families with severe acute primary Epstein-Barr virus infection. One family was reported with a homozygous p.Gln96Ter variant and the other family was reported with compound heterozygous variants - an-inframe deletion of (p.Gln381_Ala395del) and a missense variant p.Arg446Gly. p.Arg446Gly was enriched in the Finnish population (minor allele frequency = 0.0068) and was identified in homozygous state in 15 individuals from FinnGen database, which contains >400,000 individuals. Two of these individuals had hospital diagnoses of EBV infectious mononucleosis (IM). There is extensive ex vivo and in vitro data available, including mice model. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. The evidence available suggests that the rating should be borderline amber/ green due to functional data. Hence, the 'watchlist' tag has been added with amber rating.
07 Nov 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v7.6	RELB	Achchuthan Shanmugasundram commented on gene: RELB: PMID:26385063 reported three male patients from a related kindred with primary immunodeficiency and with a homozygous truncating variant in RELB (p.Tyr397Ter). All had recurrent upper and lower respiratory infections, one had ecthyma gangrenosum and developed a polyarticular arthritis with joint swelling, and another had a urinary tract infection. PMID:36402602 reported three siblings presenting with predominately severe autoimmune manifestations involving the liver, gut, lung, and skin, as well as repeated infections. They were identified with homozygous p.Pro364Leu variant. PMID:39231201 reported two unrelated adult patients with either homozygous (p.Q72Tfs*152) or compound heterozygous (p.Glu145Lys & p.Pro364Leu) loss-of-function variants. Both of them presented with combined immunodeficiency with early-onset severe bacterial, viral, and fungal diseases. Functional evidence is also available from all three publications mentioned above. This gene has been associated with immunodeficiency phenotype in OMIM (MIM #617585).
09 Oct 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v6.16	ITPR3	Achchuthan Shanmugasundram Added comment: Comment on list classification: The availability of four unrelated cases reported with the same de novo dominant-negative variant and supporting functional studies for this variant provides sufficient evidence for monoallelic MOI. The presence of two unrelated cases reported with compound heterozygous variants and supporting functional work provides sufficient evidence for biallelic MOI. Hence, the MOI was set to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" and the gene has been recommended for promotion to green rating in the next GMS update.
09 Oct 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v6.12	ITPR3	Achchuthan Shanmugasundram changed review comment from: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation. PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect.; to: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation. PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect. Neither monoallelic nor biallelic variants in this gene has been associated with immunodeficiency phenotypes either in OMIM or in Gene2Phenotype.
09 Oct 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v6.12	ITPR3	Achchuthan Shanmugasundram changed review comment from: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation. PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that; to: PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation. PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect.
14 Feb 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v4.174	ANKZF1	Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_moi' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
14 Feb 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v4.174	ANKZF1	Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
14 Feb 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v4.174	ANKZF1	Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
12 Feb 2024	Primary immunodeficiency or monogenic inflammatory bowel disease v4.163	ANKZF1	Hannah Knight gene: ANKZF1 was added gene: ANKZF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ANKZF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589 Phenotypes for gene: ANKZF1 were set to Inflammatory bowel disease Review for gene: ANKZF1 was set to AMBER Added comment: PMID: 28302725 (2017) identified two infantile-onset IBD patients with biallelic ANKZF1 variants + some functional work: One homozygous for R585Q - although this variant is very common in gnomAD One compound heterozygous for E152K and V32_Q87del Also two patients with one heterozygous variants PMID: 36857589 (2023) also identified a de novo variant (p.Leu415Val) in a young patient with IBD Sources: Literature
04 Dec 2023	Primary immunodeficiency or monogenic inflammatory bowel disease v4.125	DUT	Hannah Knight gene: DUT was added gene: DUT was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome Review for gene: DUT was set to AMBER Added comment: PMID: 28073829 (2017) - two unrelated consanguineous families with diabetes and bone marrow aplasia, both homozygous for p.Y142C PMID: 35611808 (2022) - another family, two affected children with thrombocytopenia, macrocytosis, with or without anemia, followed by non-autoimmune diabetes. Same homozygous missense variant identified as before PMID: 35931051 (2022) - identified probands who came from two independent families, had bi-allelic DUT variants, and presented with severe pancytopenia and mucocutaneous skin features. Information in supplementary materials. One patient homozygous for p.Tyr142Cys and the other compound het for p.Arg173Trp and p.Tyr227Cys Sources: Literature
03 Feb 2022	Primary immunodeficiency or monogenic inflammatory bowel disease v2.526	CRACR2A	Zornitza Stark gene: CRACR2A was added gene: CRACR2A was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: CRACR2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRACR2A were set to PMID:34908525 Phenotypes for gene: CRACR2A were set to late onset combined immunodeficiency Review for gene: CRACR2A was set to RED Added comment: PMID:34908525 - one patient compound het (missense and PTC) with late onset combined immunodeficiency (current chest infections, panhypogammaglobulinemia and CD4+T cell lymphopenia). Functional studies showed defective JNK phosphorylation, defective SOCE and impaired cytokine production. Sources: Literature
10 Aug 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.454	RGS10	Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single family with 3 affected sibs reported (PMID:34315806), who presented with short stature and immunodeficiency and harboured compound het variants in RGS10 that segregated with disease. However, the sibs also carried a heterozygous PIK3CD (E525K) variant that has previously been deemed pathogenic in Activated PI3 Kinase Delta Syndrome (APDS), a primary immunodeficiency. The variant was excluded as the father also carried the PIK3CD variant but was mostly healthy and none of the 3 affected sibs displayed the full spectrum of symptoms associated with APDS. Nonetheless, APDS is a clinically heterogeneous condition with variable penetrance among affected individuals and so the contribution of PIK3CD to the patients immune dysregulation cannot be completely ruled out. There are no further reports of an association between RGS10 variants and immunodeficiency to date, and therefore rating Red until further evidence emerges.
09 Jun 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.424	STXBP3	Arina Puzriakova changed review comment from: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Additional variants not thought to be independently deleterious by the authors, but in pathways of interest or in known VEOIBD genes, were identified in 4/5 families. * Note the previous review submitted by Kelsey Jones (GOSH) references an abstract briefly reporting on 4/5 of the families from PMID:33891011; to: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Additional variants not thought to be independently deleterious by the authors, but in pathways of interest or in known VEOIBD genes, were identified in 4/5 families. * Note the previous review submitted by Kelsey Jones (GOSH) references an abstract briefly reporting on 4 of the families from PMID:33891011
07 Jun 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.423	LRRC32	Boaz Palterer gene: LRRC32 was added gene: LRRC32 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: LRRC32 was set to Unknown Publications for gene: LRRC32 were set to 34059789 Phenotypes for gene: LRRC32 were set to Common variable immunodeficiency; Enteropathy; Lymphopenia; Reduced Tregs Penetrance for gene: LRRC32 were set to unknown Review for gene: LRRC32 was set to RED Added comment: Lehmkuhl et al. described two patients with immune dysregulation and mutations of LRRC32. Both patients carried two rare variants, however, patient 1 has both variants in cis, while patient 2 was a compound heterozygote. Reduced protein expression ex-vivo was demonstrated. Conditional mice KO model recapitulated the phenotype. Sources: Literature
12 Apr 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.412	PRIM1	Arina Puzriakova gene: PRIM1 was added gene: PRIM1 was added to Primary immunodeficiency. Sources: Literature Q2_21_rating tags were added to gene: PRIM1. Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRIM1 were set to 33060134 Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950 Review for gene: PRIM1 was set to GREEN Added comment: PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype. - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature
24 Feb 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.401	RAD50	Boaz Palterer gene: RAD50 was added gene: RAD50 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAD50 were set to 33378670 Phenotypes for gene: RAD50 were set to bone marrow failure; immunodeficiency; developmental defect Penetrance for gene: RAD50 were set to unknown Review for gene: RAD50 was set to RED Added comment: Chansel-Da Cruz et al. identified a single patient with bone marrow failure, immunodeficiency and developmental defect caused by compound heterozygous mutations in RAD50. The first mutations generate a null allele, the second is hypothesized to be hypomorphic because of the loss of a single amino acid residue in the coiled-coil domain of RAD50. Sources: Literature
29 Jan 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.392	COL7A1	Kelsey Jones changed review comment from: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). In a retrospective case series, 9 of 57 (16%) children with recessive DEBP had diarrhoea with macroscopic/microscopic features of colitis (PMID: 18363753). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert Review; to: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). In a retrospective case series, 9 of 57 (16%) children with recessive DEBP had diarrhoea with macroscopic/microscopic features of colitis (PMID: 18363753). There is additionally a recognised association between Epidermolysis Bullosa Acquisita (an autoimmune condition directed against Type VII Collagen (the COL7A1 protein product) (PMID: 23517353). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert Review
29 Jan 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.392	COL7A1	Kelsey Jones gene: COL7A1 was added gene: COL7A1 was added to Primary immunodeficiency. Sources: Expert Review Mode of inheritance for gene: COL7A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: COL7A1 were set to PMID: 18363753 Phenotypes for gene: COL7A1 were set to Very Early Onset Inflammatory Bowel Disease; Dystrophic Epidermolysis Bullosa Pruriginosa Penetrance for gene: COL7A1 were set to Incomplete Review for gene: COL7A1 was set to AMBER Added comment: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). In a retrospective case series, 9 of 57 (16%) children with recessive DEBP had diarrhoea with macroscopic/microscopic features of colitis (PMID: 18363753). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert Review
29 Jan 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.392	NPC1	Kelsey Jones changed review comment from: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). 14 patients with defects in NPC1 presenting with severe Crohn's-like intestinal inflammation described in PMID: 26953272. Mechanism suggested to involve defective bacterial handling by macrophages. Estimated 3-7% penetrance of intestinal inflammation in patients with Niemann-Pick type C disease (same reference). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert list; to: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). 14 patients with defects in NPC1 presenting with severe Crohn's-like intestinal inflammation described in PMID: 26953272. Mechanism suggested to involve defective bacterial handling by macrophages. Estimated 3-7% penetrance of intestinal inflammation in patients with Niemann-Pick type C disease (same reference). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert list
29 Jan 2021	Primary immunodeficiency or monogenic inflammatory bowel disease v2.392	NPC1	Kelsey Jones gene: NPC1 was added gene: NPC1 was added to Primary immunodeficiency. Sources: Expert list Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPC1 were set to PMID: 26953272 Phenotypes for gene: NPC1 were set to Very Early Onset Inflammatory Bowel Disease Penetrance for gene: NPC1 were set to Incomplete Review for gene: NPC1 was set to GREEN Added comment: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). 14 patients with defects in NPC1 presenting with severe Crohn's-like intestinal inflammation described in PMID: 26953272. Mechanism suggested to involve defective bacterial handling by macrophages. Estimated 3-7% penetrance of intestinal inflammation in patients with Niemann-Pick type C disease (same reference). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert list
03 Nov 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.369	FAAP24	Eleanor Williams edited their review of gene: FAAP24: Added comment: Not associated with a phenotype in OMIM. PMID: 17289582 - Ciccia et al 2007 - report that FAAP24 (C19ORF40) is a component of the Fanconi anemia (FA) core complex and interacts with the C-terminal region of FANCM. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage. PMID: 27473539 - Daschkey et al 2016 - report a homozygous missense mutation in FAAP24 (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.; Changed rating: RED; Changed phenotypes: EBV-associated lymphoproliferative disease; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
02 Sep 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.184	MCM10	Boaz Palterer gene: MCM10 was added gene: MCM10 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM10 were set to 32865517 Penetrance for gene: MCM10 were set to unknown Review for gene: MCM10 was set to AMBER Added comment: Compound heterozygous variants in minichromosomal maintenance complex member 10 (MCM10) were reported as a cause of NK-cell deficiency in a child with fatal susceptibility to CMV. Sources: Literature
30 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.139	CDC42	Zornitza Stark gene: CDC42 was added gene: CDC42 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDC42 were set to 31601675; 32303876; 32231661 Phenotypes for gene: CDC42 were set to Neonatal-onset cytopaenia with dyshaematopoiesis; autoinflammation; rash; HLH Review for gene: CDC42 was set to GREEN Added comment: PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 variant (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Yet another individual in PMID 32231661 with different de novo variant, p.Cys81Tyr who in addition developed haematological malignancy and also had syndromic features, including ID. Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737 Sources: Literature
23 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.127	ALPI	Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 29567797 - report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.; to: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.
22 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.124	BLOC1S6	Eleanor Williams changed review comment from: Provisionally associated with ?Hermansky-pudlak syndrome 9 #614171 (AR) in OMIM. BLOC1S6 is also known as PLDN and HPS9. PMID: 32245340 - Michaud et al 2020 - report 1 patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. (Abstract only accessed). PMID: 22461475 - Badolato et al 2012 - report a northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. She had thrombocytopenia and leukopenia, with normal platelet aggregation. WES found a homozygous nonsense mutation, c.232C > T (p.Q78X) in PLDN (BLOC1S6). This variant was confirmed homozygous in the patient and heterozygous in her parents by Sanger sequencing, and was associated with absent PLDN protein expression PMID: 26575419 - Yousaf et al 2016 - report a Pakistani family in which the proband had a nonsense mutation is the HPS9/PLDN gene (c.232C>T, p.Gln78). The 4-year-old female patient reported here, had Oculocutaneous albinism, photophobia, nystagmus, prolonged bleeding and clotting times, which indicate platelet dysfunction. PMID: 21665000 - Cullinane et al 2011 - RETRACTED PAPER - report 1 9-month old male patient of Indian ancestry with a homozygous c.232C>T; p.Gln78Och mutation and HPS-like phenotype. This paper has been retracted due to falsified and/or fabricated gel images which represent expression of PLDN in fibroblasts and melanocytes. Summary: 3 reports + retracted paper. 2 out of the 3 patients had abnormal platelet aggregation.; to: Provisionally associated with ?Hermansky-pudlak syndrome 9 #614171 (AR) in OMIM. BLOC1S6 is also known as PLDN and HPS9. PMID: 32245340 - Michaud et al 2020 - report 1 patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. (Abstract only accessed). PMID: 22461475 - Badolato et al 2012 - report a northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. She had thrombocytopenia and leukopenia, with normal platelet aggregation. WES found a homozygous nonsense mutation, c.232C > T (p.Q78X) in PLDN (BLOC1S6). This variant was confirmed homozygous in the patient and heterozygous in her parents by Sanger sequencing, and was associated with absent PLDN protein expression PMID: 26575419 - Yousaf et al 2016 - report a Pakistani family in which the proband had a nonsense mutation is the HPS9/PLDN gene (c.232C>T, p.Gln78). The 4-year-old female patient reported here, had Oculocutaneous albinism, photophobia, nystagmus, prolonged bleeding and clotting times, which indicate platelet dysfunction. PMID: 21665000 - Cullinane et al 2011 - RETRACTED PAPER - report 1 9-month old male patient of Indian ancestry with a homozygous c.232C>T; p.Gln78Och mutation and HPS-like phenotype. This paper has been retracted due to falsified and/or fabricated gel images which represent expression of PLDN in fibroblasts and melanocytes. Summary: 3 reports + retracted paper. 2 out of the 3 patients had abnormal platelet aggregation. The 3rd had thrombocytopenia and leukopenia, with normal platelet aggregation.
07 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.44	MPO	Sarah Leigh Classified gene: MPO as Amber List (moderate evidence)
07 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.44	MPO	Sarah Leigh Added comment: Comment on list classification: Comment on list classification: PMID 3208230 outlines the role of neutrophil extracellular traps (NETs) in the control of some pathogens including viruses, by virus capture and neutralization. In vivo treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to the CHIKV virus. Furthermore, the levels of MPO-DNA complex in acutely CHIKV-infected patients, were correlated with the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Therefore, variants that result in myeloperoxidase deficiency, may well contribute to an increased susceptiblity to viral infection. At least 9 variants have been reported in Myeloperoxidase deficiency 254600 and these could well be contributing to increased viral susceptibily.
07 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.44	MPO	Sarah Leigh Gene: mpo has been classified as Amber List (Moderate Evidence).
06 Apr 2020	Primary immunodeficiency or monogenic inflammatory bowel disease v2.43	MPO	Sarah Leigh Publications for gene: MPO were set to 15108282; 9354683; 9637725
26 Sep 2019	Primary immunodeficiency or monogenic inflammatory bowel disease v1.130	USP18	Louise Daugherty commented on gene: USP18: Pseudo TORCH syndrome: Aicardi-Goutiere like - severe intracranial haemorrhage, thrombocytopaenia, seizures, liver failure caused by interferon activation - probable green association, is it a relevant phenotype? 2 families (one homozygous, one compound het where one variant was the same as the first family with possible common ancestor) - borderline, with lack of USP18 expression - abnormal activation of the immune system (interferon) - is this a likely presentation in immunology clinic?
04 Jul 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty marked gene: MPO as ready
04 Jul 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty classified MPO as Red List (low evidence)
29 Jun 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Sophie Hambleton reviewed gene: MPO
08 May 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Sarah Leigh reviewed MPO
20 Apr 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty commented on MPO
17 Apr 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty commented on MPO
17 Apr 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty commented on MPO
17 Apr 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty reviewed MPO
17 Apr 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty Added gene to panel
13 Apr 2018	Primary immunodeficiency or monogenic inflammatory bowel disease	MPO	Louise Daugherty Added gene to panel