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Primary immunodeficiency or monogenic inflammatory bowel disease v4.191 LCP2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated cases reported now with biallelic LCP2 variants. Hence, this gene should be rated green in the next GMS review.; to: Comment on list classification: There are three unrelated cases reported with biallelic LCP2 variants and functional data available in support of the disease association. Hence, this gene should be rated green in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.191 LCP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported now with biallelic LCP2 variants. Hence, this gene should be rated green in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.188 HSPA1L Zornitza Stark reviewed gene: HSPA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: inflammatory bowel disease, MONDO:0005265, HSPA1L-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 SCGN Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases with heterozygous variants and Inflammatory bowel disease (Crohn disease). Hence, this gene should be rated amber with current evidence.
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.
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.
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.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.172 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (three unrelated cases and functional studies) for the association of this gene with disabling pansclerotic morphea of childhood (MIM #620443) and hence this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.167 STAT4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #612253 & #620443), but not in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.164 LACC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #618795), but not yet in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.161 FGL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer and reported in PMID:36006710, there are three unrelated cases and functional evidence are available for the association of biallelic CBLB variants with infantile-onset autoimmune disease (MIM #620430). Hence, this gene should be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are two unrelated families reported with monoallelic FOXI3 variant. However, the variant was inherited from apparently unaffected father in patient 2, which shows reduced penetrance. In addition, evidence from mouse model shows that FOXI3 is involved in thymus development. Hence, this gene should be rated amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (five unrelated cases) for the association of hemizygous MCTS1 variants with MSMD. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are more than three unrelated cases with either B cell deficiency and/ or hypogammaglobulinemia. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available (12 unrelated families and functional data) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram edited their review of gene: STAT6: Added comment: As reviewed by Dmitrijs Rots, PMID:36884218 reported 16 cases from 10 families with heterozygous STAT6 variants and severe early-onset allergic disease consisting of clinical features including severe, treatment-resistant atopic dermatitis (15/16) and food allergies (15/16) were the most common clinical manifestations, followed by asthma (11/16) and eosinophilic gastrointestinal disease (10/16) and severe episodes of anaphylaxis (9/16).

PMID:36216080 reported heterozygous STAT6 variant with early-onset multiorgan allergies in a family with
3 affected members and PMID:36758835 reported another child with severe atopic dermatitis, eosinophilia and elevated IgE. All these publications also provided extensive functional data which confirms the mechanism as gain-of-function.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620532), but not yet in Gene2Phenotype.; Changed publications to: 36216080, 36758835, 36884218
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 RANBP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are >3 unrelated cases reported with monoallelic variants in this gene, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.132 DUT Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. Homozygous variants identified in at least 10 individuals from 6 unrelated families (French, Egyptian, two Libyan, Sudanese and Scottish) with bone marrow failure and diabetes. DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway.

Overall there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.130 LYN Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 LYN Achchuthan Shanmugasundram changed review comment from: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence, which suggested gain of function mechanism for variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.; to: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence, which suggested gain of function mechanism for LYN variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 LYN Achchuthan Shanmugasundram changed review comment from: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence which suggested gain of function mechanism for variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.; to: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence, which suggested gain of function mechanism for variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.
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
Primary immunodeficiency or monogenic inflammatory bowel disease v4.123 IL21R Arina Puzriakova Phenotypes for gene: IL21R were changed from Immunodeficiency 56, 615207; Immunodeficiency, primary, autosomal recessive, IL21R-related; Atypical Severe Combined Immunodeficiency (Atypical SCID); Combined immunodeficiency; Omenn syndrome; Severe combined immunodeficiency (SCID); IL-21R deficiency; Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease; Immunodeficiencies affecting cellular and humoral immunity to Immunodeficiency 56, OMIM:615207
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is one patient identified with homozygous POLD3 variant (p.Ile10Thr) and reported with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. In addition, there is also functional evidence for this variant. Hence, this gene is promoted to amber rating.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is one patient identified with homozygous POLD3 variant (p.Ile10Thr) and reported with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. In addition, there is also functional evidence for this variant. Hence, this gene is promoted to amber rating.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.116 PTPN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and a Ptpn2 deficient mouse model in support of the association of PTPN2 to this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).; to: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.110 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).; to: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.110 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function variants.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).; to: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 NLRP1 Achchuthan Shanmugasundram commented on gene: NLRP1: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function variants.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 SEC61A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases in support of the association of this gene with this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.100 CD81 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and functional evidence available in support of the association of this gene to common variable immunodeficiency (MIM #613496). Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.97 CD4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and functional evidence in support of the association of this gene with this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.96 CD4 Achchuthan Shanmugasundram Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts to Immunodeficiency 79, OMIM:619238; OKT4 epitope deficiency, OMIM:613949
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 REL Achchuthan Shanmugasundram Classified gene: REL as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 REL Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 REL Achchuthan Shanmugasundram Gene: rel has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.93 REL Achchuthan Shanmugasundram Phenotypes for gene: REL were changed from Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic infections; c-Rel deficiency; Immunodeficiencies affecting cellular and humoral immunity to Immunodeficiency 92, OMIM:619652
Primary immunodeficiency or monogenic inflammatory bowel disease v4.92 REL Achchuthan Shanmugasundram Publications for gene: REL were set to 32086639; 31103457; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v4.91 REL Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: REL.
Tag Q4_23_NHS_review tag was added to gene: REL.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.91 REL Achchuthan Shanmugasundram reviewed gene: REL: Rating: GREEN; Mode of pathogenicity: None; Publications: 31103457, 34623332; Phenotypes: Immunodeficiency 92, OMIM:619652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.83 TFRC Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is shared between two different families from different geographic regions reported in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.

The 'founder-effect' tag has also been added to highlight this.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.83 TFRC Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency, they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.81 TFRC Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency, they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 TFRC Achchuthan Shanmugasundram changed review comment from: PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the combined immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls.

The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor.

Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts.

In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype.


PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel).; to: PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls.

The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor.

Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts.

In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype.


PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.78 SPI1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, PMID:33951726 is now publicly available online and have six unrelated cases and some functional data in support of the disease association. Hence, this gene can be promoted to green rating in the next GMS review.

The 'watchlist' tag has now been removed as this gene is now recommended for promotion to green rating.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.59 IRF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two different heterozygous missense variants identified from seven unrelated cases reported with hypogammaglobulinemia/ combined immunodeficiency. In addition, there is supporting functional evidence for these variants. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.57 CBLB Boaz Palterer gene: CBLB was added
gene: CBLB was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CBLB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBLB were set to 36006710
Phenotypes for gene: CBLB were set to immunedysregulation; autoimmunity; hypothyroidism; diabetes mellitus type I; vitiligo; urticaria; HLH; ITP; autoimmune hemolytic anemia
Penetrance for gene: CBLB were set to unknown
Review for gene: CBLB was set to RED
Added comment: Janssen et al. described 3 unrelated children with early-onset autoimmunity with homozygous CBLB variants. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking.

Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient’s p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.56 RELA Achchuthan Shanmugasundram Classified gene: RELA as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.56 RELA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are at least eight unrelated cases identified with monoallelic RELA variants and reported with chronic mucocutaneous ulceration (MIM #618287). Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.56 RELA Achchuthan Shanmugasundram Gene: rela has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.55 RELA Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RELA.
Tag Q4_23_NHS_review tag was added to gene: RELA.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.55 RELA Achchuthan Shanmugasundram Publications for gene: RELA were set to 28600438; 32086639; 32048120; 29305315
Primary immunodeficiency or monogenic inflammatory bowel disease v4.54 RELA Achchuthan Shanmugasundram Mode of inheritance for gene: RELA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.53 RELA Achchuthan Shanmugasundram Phenotypes for gene: RELA were changed from Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287 to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
Primary immunodeficiency or monogenic inflammatory bowel disease v4.52 RELA Achchuthan Shanmugasundram Phenotypes for gene: RELA were changed from Mucocutaneous ulceration, chronic, 618287; RelA haplosufficiency; Mucosal ulceration, impaired NFkB activation; Immunodeficiencies affecting cellular and humoral immunity to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
Primary immunodeficiency or monogenic inflammatory bowel disease v4.51 RELA Achchuthan Shanmugasundram reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.51 POLD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases and functional data in support of the association of biallelic POL1D variants with immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.45 HMOX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As listed in the review of Hannah Knight, there are more than three unrelated cases with biallelic HMOX1 variants reported with asplenia. In addition, recurrent infections, recurrent fever, generalized erythematous rash, hemolysis, inflammation, nephritis, and joint pain were reported in these cases. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.42 HMOX1 Achchuthan Shanmugasundram Added comment: Comment on publications: As listed in the review of Hannah Knight, there are more than three unrelated cases with biallelic HMOX1 variants reported with asplenia. In addition, recurrent infections, recurrent fever, generalized erythematous rash, hemolysis, inflammation, nephritis, and joint pain were reported in these cases. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.41 IRF2BP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are four unrelated cases in support of the association of monoallelic IRF2BP2 variants with immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.40 REL Hannah Knight reviewed gene: REL: Rating: AMBER; Mode of pathogenicity: None; Publications: 34623332; Phenotypes: Immunodeficiency 92; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.40 CXCR2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are five unrelated cases with biallelic CXCR2 variants. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.38 CR2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are three unrelated cases in support of the association of CR2 to immunodeficiency. Hence, this gene can be promoted to Green in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.35 RELA Hannah Knight reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: None; Publications: 28600438, 29305315, 32969189, 35412596, 36926348; Phenotypes: Autoinflammatory disease, familial, Behcet-like-3; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 ARPC5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three unrelated cases and supporting functional evidence available for the association of this gene with immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 MECOM Boaz Palterer gene: MECOM was added
gene: MECOM was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: MECOM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MECOM were set to 37407873
Phenotypes for gene: MECOM were set to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, OMIM:616738; Hypocellular bone marrow; congenital thrombocytopenia; B-cell lymphopenia; hypogammaglobulinemia; radioulnar synostosis; digit abnormalities; clubfoot; cardiac defects; facial dysmorphism
Penetrance for gene: MECOM were set to unknown
Review for gene: MECOM was set to GREEN
Added comment: Bone marrow failure syndrome included in the 2022 IUIS IEI classification. A subset of patients presents B cell deficiency and hypogammaglobulinemia. The phenotype is relevant for the panel.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 ARPC5 Boaz Palterer gene: ARPC5 was added
gene: ARPC5 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ARPC5 were set to immunodeficiency; autoimmunity; inflammation; dysmorphisms; impaired wound healing; scoliosis; pneumatoceles; anemia
Penetrance for gene: ARPC5 were set to unknown
Review for gene: ARPC5 was set to GREEN
Added comment: Nunes-Santos et al. described 2 unrelated patients from 2 kindreds woith germline biallelic null mutations in ARPC5 presenting with a complex actinopathy phenotype of increased susceptibility to infections, autoimmunity, inflammation, and dysmorphisms.
There is strong biological rationale: ARPC5 is part of the Arp2/3 complex, related to WAS in Wiskott-Aldrich syndrome and ARPC1B deficiency. Strong functional ex vivo and in vitro data is presented.
( https://doi.org/10.1038/s41467-023-39272-0 )
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 DOCK11 Boaz Palterer gene: DOCK11 was added
gene: DOCK11 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to early-onset autoimmunity; cytopenia; systemic lupus erythematosus; dermatitis; enteropathy
Penetrance for gene: DOCK11 were set to unknown
Review for gene: DOCK11 was set to GREEN
Added comment: Boussard et al. described 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients presented with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Extensive ex vivo and in vitro functional validation.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.21 TLR7 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Boaz Palterer, there are three unrelated cases and functional evidence from mouse models in support of the association of X-linked dominant variants from TLR7 gene to Systemic lupus erythematosus. Hence, this gene can be promoted to GREEN rating at the next major update.; to: Comment on list classification: As reviewed by Boaz Palterer, there are three unrelated cases and functional evidence from mouse models in support of the association of X-linked dominant variants from TLR7 gene to systemic lupus erythematosus. Hence, this gene can be promoted to GREEN rating at the next major update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.21 TLR7 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three cases and supporting functional evidence available for systemic lupus erythematosus caused by X-linked dominant variants. However, there are only two unrelated cases in support of COVID19-related immunodeficiency caused by X-linked recessive variants. Hence, the MOI should be updated from "X-LINKED: hemizygous mutation in males, biallelic mutations in females" to "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)".
Primary immunodeficiency or monogenic inflammatory bowel disease v4.20 TLR7 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are three unrelated cases and functional evidence from mouse models in support of the association of X-linked dominant variants from TLR7 gene to Systemic lupus erythematosus. Hence, this gene can be promoted to GREEN rating at the next major update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.19 TLR7 Achchuthan Shanmugasundram Phenotypes for gene: TLR7 were changed from Immunodeficiency 74, COVID19-related, X-linked, MIM# 301051 to Systemic lupus erythematosus 17, OMIM:301080; Immunodeficiency 74, COVID19-related, X-linked, OMIM:301051
Primary immunodeficiency or monogenic inflammatory bowel disease v4.17 TLR7 Achchuthan Shanmugasundram reviewed gene: TLR7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32706371, 35477763; Phenotypes: Systemic lupus erythematosus 17, OMIM:301080, Immunodeficiency 74, COVID19-related, X-linked, OMIM:301051; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.9 RHBDF2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Not yet associated with an immune phenotype in OMIM or G2P, but note that monoallelic variants in this gene are associated with tylosis.

To date, 4 individuals from 2 unrelated families have been reported (PMID: 34937930) with LoF variants in this gene and recurrent infections. Functional data includes supportive mouse model.

Rating Amber for now awaiting at least one more corroborating case (added watchlist tag)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.8 IKZF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at then next GMS panel update. At least 6 unrelated families reported with variable features of immune dysregulation who harbour different deleterious heterozygous variants in the IKZF2 gene.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.6 C2orf69 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Boaz Palterer (University of Florence). Associated with a relevant phenotype in OMIM (MIM# 619423) but is not yet listed in G2P. At least 13 unrelated families reported in literature (PMIDs: 33945503; 34038740). Sufficient cases plus zebrafish model to promote this gene to green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.583 Eleanor Williams Panel name changed from Primary immunodeficiency to Primary immunodeficiency or monogenic inflammatory bowel disease
List of related panels changed from Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; R15 to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15
Primary immunodeficiency or monogenic inflammatory bowel disease v2.580 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; AGS6; Type 1 interferonopathies; Classical AGS, BSN, SP; Autoinflammatory Disorders to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders
Primary immunodeficiency or monogenic inflammatory bowel disease v2.573 FOXI3 Boaz Palterer gene: FOXI3 was added
gene: FOXI3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 35987349
Phenotypes for gene: FOXI3 were set to T-cell lymphopenia; low TREC; thymic hypoplasia
Penetrance for gene: FOXI3 were set to Incomplete
Review for gene: FOXI3 was set to AMBER
Added comment: Ghosh et al. described 2 unrelated patients with T cell lymphopenia, positive TREC screening and thymic hypoplasia with deleterious FOXI3 variants. FOXI3 was demonstrated in mice models to be involved in thymic development.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.569 STAT6 Arina Puzriakova Added comment: Comment on list classification: Two unrelated patients with early-life onset of allergic immune dysregulation described in preprint by Sharma et al. as per review by Boaz Palterer. Red rating may be reconsidered following peer review of paper but additional cases would be required to reach a diagnostic level of evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.565 TLR8 Arina Puzriakova Added comment: Comment on list classification: Overall at least 7 unrelated families have been reported which support an association of TLR8 with immune dysfunction and autoinflammation, of which two families harboured germline variants. Functional data, including in vitro and animal model studies, corroborate pathogenicity of TLR8 variants. Therefore this gene can now be promoted to Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 EP300 Boaz Palterer gene: EP300 was added
gene: EP300 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: EP300 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EP300 were set to 32594341
Phenotypes for gene: EP300 were set to Rubinstein-Taybi Syndrome; Hypogammaglobulinemia; short stature; Intellectual disability; broad thumbs and first toes; highly arched eyebrows; long eyelashes; downslanting palpebral fissures; convex nasal ridge; low hanging columella; highly arched palate; micrognathia
Penetrance for gene: EP300 were set to unknown
Review for gene: EP300 was set to GREEN
Added comment: Saettini et al. reviewed immunological features of Rubinstein-Taybi Syndrome and found: "Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. ", making it a relevant phenotype for this panel.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 CREBBP Boaz Palterer gene: CREBBP was added
gene: CREBBP was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CREBBP were set to 32594341
Phenotypes for gene: CREBBP were set to Rubinstein-Taybi Syndrome; Hypogammaglobulinemia; short stature; Intellectual disability; broad thumbs and first toes; highly arched eyebrows; long eyelashes; downslanting palpebral fissures; convex nasal ridge; low hanging columella; highly arched palate; micrognathia
Penetrance for gene: CREBBP were set to unknown
Review for gene: CREBBP was set to GREEN
Added comment: Saettini et al. reviewed immunological features of Rubinstein-Taybi Syndrome and found: "Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. ", making it a relevant phenotype for this panel.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.554 IKBKB Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. Both inheritance patterns are associated with a relevant phenotype of primary immunodeficiency, but AR disease is more severe with earlier onset.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.536 STXBP3 Arina Puzriakova edited their review of gene: STXBP3: Added comment: The rating of this gene has been updated following NHS Genomic Medicine Service approval. It was agreed that there is enough evidence to rate as green - sufficient number of cases presenting a relevant phenotype with some functional data. However, note that several families carried potentially contributory variants in other genes.; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v2.524 PSMB9 Arina Puzriakova edited their review of gene: PSMB9: Added comment: Kanazawa et al., 2021 (PMID: 34819510) identified a further two unrelated Japanese patients with the same de novo PSMB9 heterozygous missense variant as that identified in the previous study (c.467G>A/p.G156D). Both individuals displayed severe autoinflammatory phenotypes and pulmonary hypertension and later also manifested combined immunodeficiency with periodic inflammatory exacerbation. The variant lead to impaired immunoproteasome maturation and activity, and the proteasome defect and immunodeficient phenotypes were recapitulated in Psmb9(G156D/+) mice.; Changed publications to: 33727065, 34819510; Changed phenotypes to: Proteasome-associated autoinflammatory syndrome 3, digenic, OMIM:617591
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova changed review comment from: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than >10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.; to: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.495 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than >10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.; to: Comment on list classification: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova Added comment: Comment on mode of inheritance: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated cases of immunodeficiency associated with different biallelic variants in this gene (PMID:31308374; 32562707). DEF6 is also associated with a relevant phenotype in OMIM (MIM# 619573) and should be promoted to Green at the next GMS panel update (tagged).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary immunodeficiency or monogenic inflammatory bowel disease v2.475 KMT2A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is enough evidence to promote to Green at the next GMS panel update.

Immune dysfunction, including early-onset CVID and recurrent infections, have been reported in multiple individuals with Wiedemann-Steiner syndrome. Immunopathology can be a presenting feature, and as there are sufficient unrelated cases with this phenotype, this gene should be promoted to Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.468 B2M Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic mode of inheritance is correct for Immunodeficiency 43. OMIM also has an entry for ?Amyloidosis, familial visceral, OMIM:105200 - Autosomal dominant but this phenotype is not relevant to this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.464 KMT2D Arina Puzriakova Added comment: Comment on list classification: Immunopathological manifestations are seen in ~50% of cases with KMT2D-related Kabuki syndrome. There is sufficient evidence to support this gene-disease association and therefore this gene should be promoted to Green status at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.461 ELF4 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is enough evidence to rate this gene as Green at the next GMS panel update. At least two variants identified in three unrelated individuals with autoinflammatory disease characterised by fever, oral ulcers and mucosal inflammation. Supported by functional studies and mouse model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.455 GIMAP5 Arina Puzriakova commented on gene: GIMAP5: Cannot access new publication identified by Zornitza Stark (PMID:33956074) - free text will be available from 05/01/2022. OMIM entry states that "some patients may have recurrent infections or features suggestive of an immunodeficiency" but it is unclear how many individuals were affected and to what extent. Liver dysfunction (portal hypertension, liver failure) seems to be the more prominent phenotype in these cases but currently there are no relevant PanelApp panels for this. Therefore, I will maintain the Amber rating at this time, until publications become available or further evidence emerges.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.452 RGS10 Boaz Palterer gene: RGS10 was added
gene: RGS10 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS10 were set to 34315806
Phenotypes for gene: RGS10 were set to short stature; GH deficiency; immunodeficiency; hypergammaglobulinemia; reduced lymphocyte chemotaxis
Penetrance for gene: RGS10 were set to unknown
Review for gene: RGS10 was set to AMBER
Added comment: Chinn et al. a kindred with three affected siblings presenting with short stature and immunodeficiency and segregating with biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals exhibited systemic abnormalities directly related to the RGS10 mutations, including recurrent infections, hypergammaglobulinemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Some functional data is presented.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.449 PLG Arina Puzriakova changed review comment from: Bork et al. 2018 (PMID: 28795768) found a recurrent variant (c.988A>G, p.K330E) in 13 German families with hereditary angioedema. Haplotype analysis indicated that this is a likely founder variant. However, the variant is associated with incomplete penetrance as there are several asymptomatic carriers within the families and the variant can be found at low freq in the European population in gnomAD - but has been classified as 'Pathogenic'. There is no evidence of other relevant variants but this seems to be an accepted causal variant in the literature and several subsequent publications have identified additional cases (PMIDs: 29548426; 31131012; 32066472; 32065705; 32181895). There is some data that suggests the variant might affect plasminogen glycosylation (PMIDs: 29548426; 32181895), however multiple patients have also been identified with normal plasminogen activity.; to: Bork et al. 2018 (PMID: 28795768) found a recurrent variant (c.988A>G, p.K330E) in 13 German families with hereditary angioedema. However, the variant is associated with incomplete penetrance as there are several asymptomatic carriers within the families and the variant can be found at low freq in the European population in gnomAD - but has been classified as 'Pathogenic'.

There is no evidence of other relevant variants but this seems to be an accepted causal variant in the literature and several subsequent publications have identified additional cases (PMIDs: 29548426; 29952006; 30809376; 31131012; 32066472; 32065705; 32181895; 33799813). Most cases are of European ancestry and haplotype analysis performed by the original study (Bork et al. 2018) indicated a likely founder effect. However, 2 families in Japan have since been identified indicating the variant may be found in various ethnic populations (PMID: 29987869)

There is some data that suggests the variant might affect plasminogen glycosylation (PMIDs: 29548426; 32181895), however multiple patients have also been identified with normal plasminogen activity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.441 PDCD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Rating Red as only a single patient reported to date with relevant phenotype (PMID: 34183838)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.437 OAS1 Arina Puzriakova edited their review of gene: OAS1: Added comment: Additional publication identified by Boaz Palterer (PMID:34145065) supports the inclusion of this gene as Green on this panel. There are now at least 4 different gain-of-function heterozygous variants in the OAS1 gene identified in 8 unrelated families with 10 affected individuals (P5 in PMID:34145065 and C-II-1 in PMID:29455859 refer to the same individual).; Changed rating: GREEN; Changed publications to: 34145065, 29455859; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.434 IPO8 Ivone Leong changed review comment from: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8):

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"; to: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8) panel:

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"
Primary immunodeficiency or monogenic inflammatory bowel disease v2.434 IPO8 Ivone Leong commented on gene: IPO8: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8):

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"
Primary immunodeficiency or monogenic inflammatory bowel disease v2.427 CSF2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Relevant phenotype but currently only a single family reported (PMID:33349924). Rating Red, awaiting further cases/clinical evidence to support pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.426 LRRC32 Arina Puzriakova Added comment: Comment on list classification: Novel candidate gene added by Boaz Palterer. Rating Red as currently there is not enough evidence to support this gene-disease association.

Lehmkuhl et al. 2021 (PMID: 34059789) - 2 unrelated patients with immunodeficiency were found to harbour two rare heterozygous missense variants each in the LRRC32 gene (p.Arg312Cys (recurring), p.Trp247Ter, p.Arg421Gln) - variants were in cis in one patient, but in trans in the other.

Note that a different homozygous founder variant was also found in 2 families with GDD, cleft palate, and proliferative retinopathy (PMID: 30976112) - none of these features were evident in the two cases discussed here.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.425 STXBP3 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of cases presenting a relevant phenotype with some functional data. However, given that several families carried potentially contributory variants in other genes, going to maintain an Amber rating at this time in anticipation of further cases/clinical evidence to validate the pathogenicity of this gene.
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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (6) presenting a relevant phenotype, supported by some functional data (PMID: 33951726). However, only able to access the publication abstract at this time - Rating Amber with a watchlist tag until the full text becomes available (on 2022-01-05)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 IPO8 Boaz Palterer gene: IPO8 was added
gene: IPO8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604
Phenotypes for gene: IPO8 were set to cardiovascular anomalies; joint hyperlaxity; dysmorphic features; developmental delay; immune dysregulation; allergy
Penetrance for gene: IPO8 were set to unknown
Review for gene: IPO8 was set to GREEN
Added comment: Ziegler et al. reported 12 individuals from 9 unrelated kindreds with bi-allelic loss-of-function variants in IPO8 presenting with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation. IPO8 is involved in the TGFbeta/SMAD signaling, which is a known pathway in Loeys-Dietz syndrome. Functional data in a zebrafish model.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals presenting combined immunodeficiency in association with variants in this gene. Supported by functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 SPI1 Boaz Palterer gene: SPI1 was added
gene: SPI1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPI1 were set to 33951726
Phenotypes for gene: SPI1 were set to agammaglobulinemia
Penetrance for gene: SPI1 were set to unknown
Review for gene: SPI1 was set to GREEN
Added comment: Carole le Coz et al. described 6 unrelated patients with agammaglobulinemia harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1.
The phenotype was functionally replicated by transfection of mutant PU.1
(https://rupress.org/jem/article-abstract/218/7/e20201750/212070/Constrained-chromatin-accessibility-in-PU-1?redirectedFrom=fulltext)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient number of unrelated cases (5 - PMIDs: 33224153; 28422754) with immunopathology and distinct biallelic variants in this gene to rate as Green at the next GMS panel update. Supported by functional evidence and animal model.

MPEG1 is also associated with a relevant phenotype in OMIM (MIM# 619223)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (10 - PMIDs: 33876776; 33872655) with immunopathology and biallelic variants in this gene to rate as Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 SASH3 Boaz Palterer gene: SASH3 was added
gene: SASH3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SASH3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: SASH3 were set to Combined immunodeficiency; lymphopenia; neutropenia; immunodysregulation; autoimmune cytopenias
Penetrance for gene: SASH3 were set to unknown
Review for gene: SASH3 was set to GREEN
Added comment: Delmonte et al. described three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias.
Functional data: Lentivirus-mediated transfer of SASH3 cDNA in KO Jurkat cells and patient's cell lines restored protein expression and cell proliferation. The KO mouse phenotype is compatible.
https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020008629/475781/SASH3-variants-cause-a-novel-form-of-X-linked?redirectedFrom=fulltext
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.411 ZNFX1 Boaz Palterer gene: ZNFX1 was added
gene: ZNFX1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ZNFX1 were set to mendelian susceptibility to mycobacterial disease; MSMD; monocytosis.
Penetrance for gene: ZNFX1 were set to unknown
Review for gene: ZNFX1 was set to RED
Added comment: Le Voyer et al. described two patients from two unrelated kindreds with homozygous LOF variants in the ZNFX1 gene associated with mendelian susceptibility to mycobacterial disease (MSMD) and monocytosis. ( https://www.pnas.org/content/118/15/e2102804118 )
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.411 SYK Boaz Palterer gene: SYK was added
gene: SYK was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SYK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYK were set to 33782605
Phenotypes for gene: SYK were set to immunodeficiency; hypogammaglobulinemia; multi-organ inflammatory disease
Penetrance for gene: SYK were set to unknown
Mode of pathogenicity for gene: SYK was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: SYK was set to AMBER
Added comment: Wang et al. identified six patients from unrelated kindreds with monoallelic SYK variants causing immunodeficiency and a multiorgan inflammatory disease. The variants were proven to be functionally gain-of-function. Functional GOF was confirmed in knock-in mouse experiments.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.405 GIMAP5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. 4 unrelated families with an immunodeficiency disorder and difference biallelic LoF variants in the GIMAP5 gene. Clinical improvement in Gimap5-deficient mice and a human patient was observed following treatment with rapamycin (mTORC1 inhibitor)

Although there are sufficient cases with a relevant phenotype, rating this gene Amber while pending publication of the Park 2021 article, as information can change from the initial bioRxiv upload to peer-reviewed publication. Added 'watchlist' tag and will re-curate when the paper is published.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.402 RHOG Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single case reported at present (PMID: 33513601). Relevant phenotype and some supportive functional data included.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 SLC9A3 Kelsey Jones gene: SLC9A3 was added
gene: SLC9A3 was added to Primary immunodeficiency. Sources: Expert Review
Mode of inheritance for gene: SLC9A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC9A3 were set to PMID: 26358773
Phenotypes for gene: SLC9A3 were set to Very Early Onset Inflammatory Bowel Disease; Congenital sodium diarrhoea
Penetrance for gene: SLC9A3 were set to Incomplete
Review for gene: SLC9A3 was set to AMBER
Added comment: Described as a monogenic cause of VEOIBD (recognised criteria for the R15 panel). 2 patients from unrelated families in a series of 9 cases with SLC9A3-related congenital sodium diarrhoea developed intestinal inflammation/IBD (PMID: 26358773). GWAS have indicated a strong association between SLC9A3 and IBD, and there are supportive mouse models (reviewed in PMID: 26358773).Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580).
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 STXBP3 Kelsey Jones gene: STXBP3 was added
gene: STXBP3 was added to Primary immunodeficiency. Sources: Expert Review
Mode of inheritance for gene: STXBP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STXBP3 were set to PMID: 33346580
Phenotypes for gene: STXBP3 were set to Very Early Onset Inflammatory Bowel Disease; Sensorineural hearing loss
Penetrance for gene: STXBP3 were set to unknown
Review for gene: STXBP3 was set to AMBER
Added comment: Described as a monogenic cause of VEOIBD (recognised criteria for the R15 panel) in a report published in abstract form (DOI: https://doi.org/10.1053/j.gastro.2017.11.120). 8 patients from 4 unrelated families with defects in STXBP3 reportedly associated with VEO-IBD, bilateral sensorineural hearing loss, and impaired cytotoxic T-lymphocyte function (granule release, stimulated CD107a upregulation). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580).
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 RNU7-1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Boaz Palterer. Currently only one paper (PMID: 33230297) indicating pathogenicity of RNU7-1 variants, which also reports on a healthy individual with biallelic rare variants in this gene. Rating Amber awaiting further publications/clinical evidence to corroborate this gene-disease association (added 'watchlist' tag); to: Comment on list classification: New gene added by Boaz Palterer. Rating Amber with recommendation of review by the GMS team with regards to phenotypic fit for the PID panel - Aicardi-Goutieres syndrome genes are Green on this panel. Sufficient unrelated cases, supported by functional analysis (PMID: 33230297), to promote to Green if appropriate.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 RNU7-1 Arina Puzriakova changed review comment from: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome which is relevant to this panel. 4/12 variants were observed in 2 or more families. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
However, RNU7-1 variants have also been reported in control populations. 7 variants are recorded in gnomAD at a frequency of ≤0.005, and screening of 663 controls yielded 1 healthy individual with biallelic rare variants in RNU7-1 (Supplementary Table 4).; to: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including upregulated interferon signalling in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.390 TLR8 Arina Puzriakova Added comment: Comment on list classification: 6 unrelated individuals with relevant phenotype, associated with variants in this gene (https://doi.org/10.1182/blood.2020009620). However, 5 cases had somatic mosaicism and this panel is not appropriate for somatic variant detection due to coverage. Therefore, rating Red but this may be reviewed if additional cases with germline variants emerge.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.387 TLR8 Boaz Palterer gene: TLR8 was added
gene: TLR8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR8 was set to Other
Publications for gene: TLR8 were set to 10.1182/blood.2020009620
Phenotypes for gene: TLR8 were set to neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure
Penetrance for gene: TLR8 were set to unknown
Mode of pathogenicity for gene: TLR8 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TLR8 was set to AMBER
Added comment: Aluri et al. (Blood 2020, 10.1182/blood.2020009620) identified six unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and bone marrow failure associated with three different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8).
The variants are functionally gain-of-function and all patients are males, it's unclear if heterozygous females are affected. Both germline and somatic variants have been identified, but somatic mutations appear to be prominent.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Added comment: Comment on list classification: Hypogammaglobulinemia has been reported in some cases which is relevant to this panel. However, patients are more likely to be recognised for skeletal muscle features of the disease presentation. Furthermore, the review is relevant to the CCTG repeat expansion rather than small variants (i.e. LoF, missense, etc) in this gene and therefore maintaining the Red rating on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Relevant phenotype but rating Red as this panel is not appropriate for somatic variant detection due to the coverage and therefore variants are unlikely to be picked up by our current pipeline (added 'somatic' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) - at least 7 unrelated families with immune dysfunction associated with variants in this gene, as well as supportive functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 SOCS1 Zornitza Stark edited their review of gene: SOCS1: Added comment: PMID 33087723: Ten individuals from 5 unrelated families with LOF variants in this gene and early-onset autoimmunity. Functional data indicates cytokine hypersensitivity of immune cells.; Changed publications: 32499645, 10490099, 10490100, 33087723; Changed phenotypes: Common variable immunodeficiency, Early-onset autoimmunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 RELB Eleanor Williams Source Other was added to RELB.
Publications for gene RELB were updated from 32048120; 26385063; 32086639 to 26385063; 32086639; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 RELB Eleanor Williams reviewed gene: RELB: Rating: ; Mode of pathogenicity: ; Publications: 26385063; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.204 RELN Eleanor Williams gene: RELN was added
gene: RELN was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RELN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RELN were set to 32001840
Phenotypes for gene: RELN were set to Ankylosing spondylitis
Review for gene: RELN was set to RED
Added comment: PMID: 32001840 - Garshasbi et al 2020. Report a large consanguineous Iranian family with ankylosing spondylitis and a heterozygous variant in RELN.

After consultation with the Genomics England clinical team it was decided to add this gene to the PID panel with a red rating until the phenotype association is confirmed. In general there is local spinal inflammation, rather than a systemic inflammatory response.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.193 TLR7 Arina Puzriakova Added comment: Comment on list classification: Phenotype is more relevant to a severe COVID-19 clinical course - this gene is already Green on the COVID-19 research panel (Version 1.69).
Therefore, rating Amber, but this can be reviewed if new evidence emerges.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.191 FNIP1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 5 unrelated cases with immunodeficiency associated with biallelic FNIP1 variants, as well as supportive functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.190 TOM1 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but currently only a single family reported. Therefore, rating Red awaiting additional cases/clinical evidence to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.189 TNFSF13 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but currently only a single case. Therefore, rating Red awaiting additional cases/clinical evidence to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 TET2 Arina Puzriakova changed review comment from: PMID: 32518946 (2020) - Three cases from two unrelated consanguineous families with immunodeficiency and lymphoproliferative disease, associated with homozygous variants (c.4145A>G, p.H1382R and c.4894C>T,
p.Q1632*) in the TET2 gene. Molecular studies showed that the variants result in altered DNA methylation and B-cell maturation, as well as skewed T-cell differentiation and hematopoiesis.; to: PMID: 32518946 (2020) - Three cases from two unrelated consanguineous families with immunodeficiency and lymphoproliferative disease, associated with homozygous variants (c.4145A>G, p.H1382R and c.4894C>T, p.Q1632*) in the TET2 gene. Molecular studies showed that the variants result in altered DNA methylation and B-cell maturation, as well as skewed T-cell differentiation and hematopoiesis.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.187 MCM10 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.186 MAPK8 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.185 CTNNBL1 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 TLR7 Zornitza Stark gene: TLR7 was added
gene: TLR7 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TLR7 were set to 32706371
Phenotypes for gene: TLR7 were set to Immunodeficiency 74, COVID19-related, X-linked, MIM# 301051
Review for gene: TLR7 was set to GREEN
Added comment: Four affected individuals from two unrelated families and some functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.182 NCKAP1L Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least six unrelated families with distinct variants in this gene presenting the relevant phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Added comment: Comment on list classification: Upgraded rating from Amber to Green following advice from Helen Brittain (Genomics England Clinical Team): There appear to be three unrelated families with variants and hypogammaglobulinaemia. I think this is a relevant phenotype for immune dysfunction.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 20 families. PMID 30374066 haplotype analysis identified at least 12 distinct chromosome backgrounds within 7 families homozygous for rs184868814, suggestive of recurrant occurrence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 5 unrelated families (two families with the same variant had shared ethnic heritage PMID 31040185).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases, together with supportive functional studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.159 FCHO1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. At least 5 biallelic variants reported in at least 5 unrelated cases, together with supportive functional studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.153 CDC42 Ivone Leong Added comment: Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a suggested Green rating based on evidence she has provided.

As well as the listed cases there is another paper (PMID: 31271789) describing 4 unrelated cases with de novo variants in CDC42 (p.C188Y, p.R186C, p.*192C*24). The patients predominantly had systemic autoinflammatory disease and development of HLH.

Therefore there is enough evidence to rate this gene as Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.142 CD4 Ivone Leong Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949 to Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 CD4 Zornitza Stark reviewed gene: CD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 31781092; Phenotypes: Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.137 PAX1 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Green based on 2 papers (PMID:28657137 and PMID:32111619): 8 individuals from 4 unrelated families with SCID.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.132 DBR1 Catherine Snow Added comment: Comment on list classification: DBR1 identified by expert review. DBR1 variants identified in unrelated patients from different ethnicities, each had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus
Primary immunodeficiency or monogenic inflammatory bowel disease v2.130 EFL1 Catherine Snow Added comment: Comment on list classification: EFL1 identified by expert review. Promoting from Grey to Green, sufficient number of unrelated individuals with Shwachman-Diamond like syndrome.
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.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 BCL11B Eleanor Williams changed review comment from: Associated with Immunodeficiency 49 #617237 (AD) in OMIM.

PMID: 29985992 - Lessel et al 2018 - identified de novo heterozygous germline mutations in BCL11B in nine unrelated patients, namely six frameshift, two nonsense and one missense mutation. A further patient inherited a heterozygous frameshift mutation, p.(Asp534Thrfs*29), transmitted from an affected mother with. All analysed individuals exhibited developmental delay and intellectual disability and a severe reduction of peripheral ILC2s and impaired T cell development, but no overt immune deficiency. Patient E:II-1 was the only patient with suspected immunodeficiency diagnosed upon newborn screening. Other de-novo variants were also detected in some patients.

PMID: 27959755 - Punwani et al 2016 - an infant with "leaky" SCID as well as craniofacial and dermal abnormalities and the absence of a corpus callosum. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The mutant protein had dominant negative activity, which prevented the wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration. bcl11ba-deficient zebrafish recapitulated the phenotype.; to: Associated with Immunodeficiency 49 #617237 (AD) in OMIM.

PMID: 29985992 - Lessel et al 2018 - identified de novo heterozygous germline mutations in BCL11B in nine unrelated patients, namely six frameshift, two nonsense and one missense mutation. A further patient inherited a heterozygous frameshift mutation, p.(Asp534Thrfs*29), transmitted from an affected mother with. All analysed individuals exhibited developmental delay and intellectual disability and a severe reduction of peripheral ILC2s and impaired T cell development, but no overt immune deficiency. Patient E:II-1, with a missense variant, was the only patient with suspected immunodeficiency diagnosed upon newborn screening. Other de-novo variants were also detected in some patients.

PMID: 27959755 - Punwani et al 2016 - an infant with "leaky" SCID as well as craniofacial and dermal abnormalities and the absence of a corpus callosum. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The mutant protein had dominant negative activity, which prevented the wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration. bcl11ba-deficient zebrafish recapitulated the phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.123 C17orf62 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. 6 Icelandic related cases with same variant, another variant identified in Saudia Arabian individual with related phenotype. Mouse model and functional studies support the role of this gene in Chronic granulomatous disease
Primary immunodeficiency or monogenic inflammatory bowel disease v2.108 SLC7A7 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. SLC7A7 causes lysinuric protein intolerance (LPI) and immunodeficiency is one of the phenotypes. There are >3 unrelated cases reported on OMIM.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.107 RELA Ivone Leong Classified gene: RELA as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.107 RELA Ivone Leong Gene: rela has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.87 RECQL4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 3 unrelated cases in which immunodeficiecy was a feature (PMID 16630167; 21143835; 26064716). In addition RECQL4 variants have been implicated in Acrodermatitis Enteropathica caused by SLC39A4 (p.Gly512Trp)(PMID 30174688)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 REL Zornitza Stark reviewed gene: REL: Rating: RED; Mode of pathogenicity: None; Publications: 31103457; Phenotypes: Combined immunodeficiency, T cells: normal, decreased memory CD4, poor proliferation, B cells: low, mostly naive, few switched memory B cells, impaired proliferation, Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms, Defective innate immunity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 RELA Zornitza Stark reviewed gene: RELA: Rating: AMBER; Mode of pathogenicity: None; Publications: 28600438, 29305315; Phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287, Impaired NFkB activation, reduced production of inflammatory cytokines, autoimmune cytopaenias; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PAX1 Zornitza Stark gene: PAX1 was added
gene: PAX1 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: PAX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX1 were set to 32111619
Phenotypes for gene: PAX1 were set to Syndromic SCID; dysmorphism; ear abnormalities; otofaciocervical syndrome
Review for gene: PAX1 was set to GREEN
gene: PAX1 was marked as current diagnostic
Added comment: 6 individuals from three unrelated families.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 EFL1 Zornitza Stark gene: EFL1 was added
gene: EFL1 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: EFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFL1 were set to 28331068; 31151987
Phenotypes for gene: EFL1 were set to Shwachman-Diamond syndrome 2, MIM# 617941
Review for gene: EFL1 was set to GREEN
gene: EFL1 was marked as current diagnostic
Added comment: Six unrelated families reported, two had the same homozygous variant, one family single variant plus 'expression defect' identified. Neutropaenia is part of the phenotype, and other SDS genes are part of the PID panel.
Sources: Expert list
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.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.42 IFNAR1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. However, the publications listed below give evidence that the three LOF variants in two unrelated cases are associated with an adverse reaction to attenuated virus vaccines, which are rescued by wt IFNAR1 protein in vitro.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.37 TMEM173 Ellen McDonagh Added comment: Comment on publications: Additional evidence added to the publication list, provided by Abdelazeem Elhabyan. Comments from Abdelazeem Elhabyan: GenBank - https://www.ncbi.nlm.nih.gov/gene?term=(human%5BOrganism%5D)%20AND%20TMEM173%5BGene%20Name%5D) This gene encodes a five transmembrane protein that functions as a major regulator of the innate immune response to viral and bacterial infections. The encoded protein is a pattern recognition receptor that detects cytosolic nucleic acids and transmits signals that activate type I interferon responses.

Hypothesis:
This gene is involved in interferon 1 pathway which is directly related to viral innate immune response. Upregulation may be associated with a protective effect or autoinflammatory response with aggravating effect. This is to be determined by clinical trials.

Highest organ of expression is the lung in genbank (Pneumonia caused by corona) RPKM ,\mean is 37

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069765/

Extracellular vesicles released by virally infected cells(HSV) that carry STING can induce protective effect against viral replication in neighbouring non infected cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146713/

Virulent Poxviruses Inhibit DNA Sensing by Preventing STING Activation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923072/
The gene is involved in acute pancreatitis in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112120/
Primary immunodeficiency or monogenic inflammatory bowel disease v2.36 RELA Louise Daugherty reviewed gene: RELA: Rating: AMBER; Mode of pathogenicity: ; Publications: 28600438, 29305315; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.36 REL Louise Daugherty reviewed gene: REL: Rating: AMBER; Mode of pathogenicity: ; Publications: 31103457; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.35 RELA Louise Daugherty Publications for gene RELA were updated from 32048120; 32086639 to 28600438; 32086639; 32048120; 29305315
Primary immunodeficiency or monogenic inflammatory bowel disease v2.35 REL Louise Daugherty Publications for gene REL were updated from 32048120; 32086639 to 32086639; 31103457; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 RELB Louise Daugherty Source IUIS Classification December 2019 was added to RELB.
Added phenotypes Recurrent infectionsImmunodeficiencies affecting cellular and humoral immunity for gene: RELB
Publications for gene RELB were updated from 26385063 to 32048120; 26385063; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 IRAK1 Louise Daugherty Source IUIS Classification December 2019 was added to IRAK1.
Mode of inheritance for gene IRAK1 was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Added phenotypes Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 for gene: IRAK1
Publications for gene IRAK1 were updated from 28069966 to 32048120; 28069966; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.30 RAC2 Louise Daugherty Phenotypes for gene: RAC2 were changed from T-B- SCID; T-B+ SCID; Neutrophil immunodeficiency syndrome 608203; Neutrophil immunodeficiency syndrome; RAS-related C3 Bolutinum toxin substrate 2 deficiency (RAC2); Poor wound healing, leukocytosis; Congenital defects of phagocyte number or function to T-B- SCID; T-B+ SCID; Neutrophil immunodeficiency syndrome 608203; Neutrophil immunodeficiency syndrome; RAS-related C3 Bolutinum toxin substrate 2 deficiency (RAC2); Poor wound healing, leukocytosis; Congenital defects of phagocyte number or function; Reticular dysgenesis; Recurrent sinopulmonary infections, selective IgA defiency; poststreptococcal glomerulonephritis; urticaria
Primary immunodeficiency or monogenic inflammatory bowel disease v2.13 RELA Louise Daugherty gene: RELA was added
gene: RELA was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RELA were set to 32048120; 32086639
Phenotypes for gene: RELA were set to Mucocutaneous ulceration, chronic, 618287; RelA haplosufficiency; Mucosal ulceration, impaired NFkB activation; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.13 REL Louise Daugherty gene: REL was added
gene: REL was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: REL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REL were set to 32048120; 32086639
Phenotypes for gene: REL were set to Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic infections; c-Rel deficiency; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.0 ZNF341 Owen Siggs gene: ZNF341 was added
gene: ZNF341 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZNF341 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF341 were set to 29907690; 29907691
Phenotypes for gene: ZNF341 were set to Hyper-IgE syndrome
Review for gene: ZNF341 was set to GREEN
Added comment: Ten unrelated families with nonsense or frameshift variants.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.0 IL6R Owen Siggs gene: IL6R was added
gene: IL6R was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IL6R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL6R were set to 31235509
Phenotypes for gene: IL6R were set to Recurrent infections; Hyper-IgE; Eczema
Review for gene: IL6R was set to GREEN
Added comment: Two unrelated cases with homozygous variants (frameshift or missense) and compelling functional evidence.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.0 IL6ST Owen Siggs gene: IL6ST was added
gene: IL6ST was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IL6ST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL6ST were set to 31235509
Phenotypes for gene: IL6ST were set to Recurrent infections; Abnormal acute-phase responses; Elevated IgE; Eczema; Eosinophilia
Review for gene: IL6ST was set to GREEN
Added comment: Two unrelated cases with homozygous variants (nonsense or missense), with functional evidence of causation.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.0 SNORA31 Owen Siggs gene: SNORA31 was added
gene: SNORA31 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SNORA31 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SNORA31 were set to 31806906
Phenotypes for gene: SNORA31 were set to Herpes simplex encephalitis
Review for gene: SNORA31 was set to GREEN
Added comment: Five unrelated families, four heterozygous variants in small nucleolar RNA gene.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.0 RC3H1 Owen Siggs gene: RC3H1 was added
gene: RC3H1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RC3H1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RC3H1 were set to PMID: 31636267
Phenotypes for gene: RC3H1 were set to Hemophagocytic lymphohistiocytosis
Penetrance for gene: RC3H1 were set to unknown
Added comment: Single case, homozygous nonsense in consanguineous kindred, clinical phenotype resembling HLH (PMID: 31636267). Convincing functional evidence of causation with phenotypic similarities to mouse model. Promote to Green List once second unrelated case identified.
Sources: Literature
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?
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 SAMD9L Louise Daugherty commented on gene: SAMD9L: Ataxia pancytopaenia syndrome - 2 unrelated families, no functional work - amber association, is there an immunological phenotype?
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 RET Louise Daugherty commented on gene: RET: MEN2 / MTC - ?relevant phenotype / Hirschsprung in LOF
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 PTEN Louise Daugherty commented on gene: PTEN: Cowden (macrocephaly, variable GDD, skin features, malignancy risk) - some patients reported to have primary immunodef / hypogammaglob. / lymphopaenia / T&B cell abn. / susceptibility to infections). Green association - relevant phenotype?
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 PSMA3 Louise Daugherty commented on gene: PSMA3: ?Proteasome-associated autoinflammatory syndrome 1, digenic. Two unrelated children het
for this and another gene (PSMB8) hence ?digenic - amber on association
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 NRAS Louise Daugherty commented on gene: NRAS: Noonan (plus malignancies in somatic variants): ?relevant phenotype
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 GUCY2C Louise Daugherty commented on gene: GUCY2C: AD: diarrhoea 6, relatively mild with potential IBD association one family ?GOF, vs AR: meconium ileus, one family. ?Phenotypic relevance and also amber on association
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 GTF2H5 Louise Daugherty commented on gene: GTF2H5: Trichothiodystrophy: green association (3 unrelated cases), ?phenotype relevant: recurrent infective exacerbations of asthma
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 ERCC3 Louise Daugherty commented on gene: ERCC3: Trichothiodystrophy / XP: DNA repair - short, microcephaly, delay, ectodermal features with photosensitivity. Omim 2 sibs in a consang family Jan 17 - amber association, relevant phenotype?)
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 ERCC2 Louise Daugherty commented on gene: ERCC2: Trichothiodystrophy / XP: DNA repair - short, microcephaly, delay, ectodermal features and recurrent infections - green association, probably a relevant phenotype?)
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 CFB Louise Daugherty commented on gene: CFB: ?Complement factor B deficiency: one family, relevant phenotype - ?amber
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 CARD14 Louise Daugherty commented on gene: CARD14: Psoriasis ?relevant phenotype (also some evidence of presence in controls - is it useful clinically?
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 BLOC1S6 Louise Daugherty commented on gene: BLOC1S6: ?Hermansky-Pudlak: one patient - amber, relevant phenotype
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 AP1S3 Louise Daugherty commented on gene: AP1S3: Pustular psoriasis susceptibility: variant seen in cases > controls. Is this a relevant phenotype / is this clinically useful?
Primary immunodeficiency or monogenic inflammatory bowel disease v1.127 MBL2 Louise Daugherty commented on gene: MBL2: relevant to 5-10% of the population and that there are three specific missense variants described. Rated Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.127 USP18 Tracy Briggs edited their review of gene: USP18: Added comment: I think USP18 should be green: five PTS patients from two unrelated families; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v1.120 SH3BP2 Louise Daugherty commented on gene: SH3BP2: OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): SH3BP2 .PanelApp HGNC gene symbol check: SH3BP2 . IUIS Disease: Cherubism . IUIS Inheritance: AD .T cells: Variable, .B cells: N/A, .IUIS Other affected cells: Stroma cells, bone cells. IUIS Associated features: Bone degeneration in jaws. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Non-Inflammasome Related Conditions
Primary immunodeficiency or monogenic inflammatory bowel disease v1.101 NLRP1 Louise Daugherty changed review comment from: Comment on list classification: Upgraded from Red to Amber. This is a relevant phenotype but there is not enough evidence in the literature to date (only two cases) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.; to: Comment on list classification: Upgraded from Red to Amber. This is a relevant phenotype but there is not enough evidence in the literature to date (only two reported cases) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.101 NRAS Louise Daugherty commented on gene: NRAS: This is a relevant phenotype but there is not enough evidence in the literature to date (PMID: 17517660 seems to report one person with NRAS and this phenotype) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.101 NLRP1 Louise Daugherty changed review comment from: Comment on list classification: This is a relevant phenotype but there is not enough evidence in the literature to date (only two cases) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.; to: Comment on list classification: Upgraded from Red to Amber. This is a relevant phenotype but there is not enough evidence in the literature to date (only two cases) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.101 NLRP1 Louise Daugherty Added comment: Comment on list classification: This is a relevant phenotype but there is not enough evidence in the literature to date (only two cases) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.99 HPS1 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (LNGLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.; to: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (London North GLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.99 HPS4 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (LNGLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.; to: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (London North GLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.99 HPS6 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (London North GLH).
Primary immunodeficiency or monogenic inflammatory bowel disease v1.98 HPS1 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating and phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (LNGLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.; to: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (LNGLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.98 HPS4 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however The Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating, the phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (LNGLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.96 HPS1 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Green. There is strong evidence for gene:disease association, the query previously for this gene was the phenotype, however Immunology Specialist Test Group during webex call 28th March 2019 recommended Green rating and phenotype was relevant to the panel for GMS, and further confirmed in follow up email on 20th June (North West GLH) and 6th September (LNGLH).
The Specialist Test Group all agreed that there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.95 CFB Louise Daugherty commented on gene: CFB: This is a relevant phenotype but there is not enough evidence in the literature to date (one case) and there has been no further evidence in terms of unpublished cases other than a Green rating recommendation from the Immunology Specialist Test Group. To remain Amber unless further supporting evidence from the Test Group
Primary immunodeficiency or monogenic inflammatory bowel disease v1.54 Louise Daugherty List of related panels changed from Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; R15
Primary immunodeficiency or monogenic inflammatory bowel disease v1.51 USP18 Louise Daugherty changed review comment from: Comment on publications: Added publications PMID: 31272490, PMID:27325888 suggested by Tracy Briggs (NWGLH) on behalf of the Specialist Test Group to support inclusion of this gene on the panel and a Green rating. Flagged for further discussion with the Specialist Test Group as conflicts with the Amber rating agreed in the webex 28th March 2019; to: Comment on publications: Added publications PMID: 31272490, PMID:27325888 suggested by Tracy Briggs (NWGLH) on behalf of the Specialist Test Group to support inclusion of this gene on the panel and a Green rating. : five PTS patients from two unrelated families. Flagged for further discussion with the Specialist Test Group as conflicts with the Amber rating agreed in the webex 28th March 2019
Primary immunodeficiency or monogenic inflammatory bowel disease v1.28 Ellen McDonagh Panel name changed from Primary immunodeficiency disorders to Primary immunodeficiency
List of related panels changed from A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Primary immunodeficiency or monogenic inflammatory bowel disease v1.27 SPPL2A Louise Daugherty Added comment: Comment on list classification: New gene recommended by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Primary immunodeficiency or monogenic inflammatory bowel disease v1.25 Louise Daugherty List of related panels changed from A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis to A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection
Primary immunodeficiency or monogenic inflammatory bowel disease v1.22 Ellen McDonagh List of related panels changed from A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID to A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis
Primary immunodeficiency or monogenic inflammatory bowel disease v1.20 NFAT5 Louise Daugherty commented on gene: NFAT5: watch tag added - there is supportive evidence in terms of cellular studies in mice that partially reproduce the immune phenotype with haploinsufficiency of this gene, Watchlist tag added in relation for further evidence of CNV / SNVs to promote it to green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.19 RAC2 Louise Daugherty commented on gene: RAC2: Zornitza Stark (VCGS) , pers. comm. notes 2 families/functional evidence and rates the gene Green. However, there is only a single variant reported and confirmed in the literature NM_002872.4(RAC2):c.169G>A (p.Asp57Asn) that result in Neutrophil immunodeficiency syndrome. There is a second variant reported in clinvar by a Invitae, but although the phenotype is attributed to Neutrophil immunodeficiency syndrome, the affected status of the patient is described as 'unknown', so it was decided to keep this gene Amber until more robust evidence is published to support gene-disease relationship
Primary immunodeficiency or monogenic inflammatory bowel disease v1.17 RIPK1 Louise Daugherty Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Primary immunodeficiency or monogenic inflammatory bowel disease v1.16 RIPK1 Louise Daugherty edited their review of gene: RIPK1: Added comment: From OMIM : Lourenco et al. (2018) PMID: 30026316 reports 4 patients from 3 unrelated consanguineous families with immunodeficiency-57 identifying homozygous loss-of-function mutations in the RIPK1 gene. The variants segregated with the disorder in the families and were not found in the gnomAD database. Functional studies of patient cells showed impaired mitogen-activated protein kinase activation, impaired phosphorylation of downstream signaling molecules, impaired proinflammatory signaling downstream of TNFR1 and TLR3 and defective secretion of certain cytokines. Similar results were observed in vitro in a monocyte-like cell line with CRISPR/Cas9-mediated knockdown of RAPK1. The findings indicated that RIPK1 plays a critical role in the human immune system.; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v1.15 RIPK1 Louise Daugherty Added comment: Comment on publications: PMID:30026316 reported four patients from three unrelated families with complete RIPK1deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.13 RASGRP1 Louise Daugherty Added comment: Comment on list classification: Changed status from Red to Green from external review and reference to two recent publications, Somekh I et al., PMID: 30030704 (2018) and Winter S et al., PMID: 29282224, there are more than three unrelated families described with immunodeficiency phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.9 CD247 Louise Daugherty commented on gene: CD247: Additional external review this gene was reviewed again. There are two pathogenic germline variants in Clinvar, the first NM_198053.2(CD247):c.301C>T (p.Gln101Ter) pathogenic variant is the same variant reported in PMID:16672702. However, it is not clear if this is strong enough evidence for three unrelated cases, as there is not a clear indication based on the information supplied to ClinVar wether these are two different cases, or are the same.
To be referred to clinical team again, in view of green review (pers. comm with Zornitza Stark, VCGS) in addition to comment below.
1) NM_198053.2(CD247):c.301C>T (p.Gln101Ter) reported from GeneDx clinical lab, no disorder associated but is the same pathogenic variant as reported in PMID:16672702
2) NM_198053.2(CD247):c.51dup (p.Ile18Aspfs) which is associated to Immunodeficiency due to defect in cd3-zeta reported from Invitae clinical lab
Primary immunodeficiency or monogenic inflammatory bowel disease RELB Louise Daugherty edited their review of gene: RELB
Primary immunodeficiency or monogenic inflammatory bowel disease RELB Louise Daugherty marked gene: RELB as ready
Primary immunodeficiency or monogenic inflammatory bowel disease RELB Louise Daugherty commented on gene: RELB
Primary immunodeficiency or monogenic inflammatory bowel disease RELB Sophie Hambleton reviewed gene: RELB