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Primary immunodeficiency or monogenic inflammatory bowel disease v4.197 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Immunodeficiency 33, 300636; Ectodermal dysplasia, hypohidrotic, with immune deficiency 300291; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; Immunodeficiency, isolated, 300584; Invasive pneumococcal disease, recurrent isolated, 2,300640; Defects of TLR/NFkappa-B signalling; Anhidrotic ectodermal dysplasia (in some), various infections (bacteria, mycobacteria, viruses and fungi), colitis, conical teeth, variable defects of skin, hair and teeth, monocyte dysfunction; Combined immunodeficiencies with associated or syndromic features to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291; Immunodeficiency 33, OMIM:300636
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 v4.190 LCP2 Achchuthan Shanmugasundram Phenotypes for gene: LCP2 were changed from SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation to ?Immunodeficiency 81, OMIM:619374
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 v4.171 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 v4.160 FGL2 Achchuthan Shanmugasundram Phenotypes for gene: FGL2 were changed from immunedysregulation; autoimmunity; arthritis; Treg dysfunction; leukocytoclastic vasculitis to autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v4.159 CBLB Achchuthan Shanmugasundram Phenotypes for gene: CBLB were changed from immunedysregulation; autoimmunity; hypothyroidism; diabetes mellitus type I; vitiligo; urticaria; HLH; ITP; autoimmune hemolytic anemia to Autoimmune disease, multisystem, infantile-onset, 3, OMIM:620430
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 v4.134 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 v4.122 PRF1 Arina Puzriakova Phenotypes for gene: PRF1 were changed from Hemophagocytic lymphohistiocytosis, familial 2, 603553; FHL2; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH2; HLH2; Fever, HSM, Hemophagocytic lymphohistiocytosis (HLH), cytopenias; Diseases of Immune Dysregulation to Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553
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 v4.108 MAN2B2 Achchuthan Shanmugasundram Phenotypes for gene: MAN2B2 were changed from to congenital disorder of glycosylation, MONDO:0015286
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 MAN2B2 Achchuthan Shanmugasundram reviewed gene: MAN2B2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v4.99 CD81 Achchuthan Shanmugasundram Phenotypes for gene: CD81 were changed from Common variable immunodeficiency disorders (CVID); Immunodeficiency, common variable 6, 613496; hypogammaglobulinaemia; CD81 deficiency; Isolated IgG subclass deficiency; Predominantly Antibody Deficiencies; Recurrent infections, may have glomerulonephritis to Immunodeficiency, common variable, 6, OMIM:613496
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 v4.94 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 v4.83 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 v4.73 JAK1 Achchuthan Shanmugasundram Phenotypes for gene: JAK1 were changed from Susceptibility to mycobacteria and viruses, urothelial carcinoma; Hypereosinophilic syndrome; Defects in Intrinsic and Innate Immunity; Diseases of Immune Dysregulation; HSM, eosinophilic enteritis, thyroid disease, poor growth, viral infections; HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections to Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999
Primary immunodeficiency or monogenic inflammatory bowel disease v4.68 JAK1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of monoallelic variants in this gene to Autoinflammation, immune dysregulation, and eosinophilia (MIM #618999). However, the evidence for the association of biallelic variants is not sufficient for green rating. Hence, the MOI is set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.67 JAK1 Achchuthan Shanmugasundram reviewed gene: JAK1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28008925, 28111307, 30671064, 32750333, 34496019, 35046931; Phenotypes: Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 MCTS1 Boaz Palterer gene: MCTS1 was added
gene: MCTS1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: MCTS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: MCTS1 were set to MSMD; non tubercular mycobacteria infection; BCGtis; BCG infection
Penetrance for gene: MCTS1 were set to Complete
Review for gene: MCTS1 was set to GREEN
Added comment: Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria
https://doi.org/10.1016/j.cell.2023.09.024

Bohlen et al. identified 6 male subjects from 5 kindreds with LOF MCTS-1 variants with MSMD.
Extensive ex-vivo functional validation and mouse model.
Sources: Literature
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 v4.57 FGL2 Boaz Palterer gene: FGL2 was added
gene: FGL2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: FGL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGL2 were set to 36243222
Phenotypes for gene: FGL2 were set to immunedysregulation; autoimmunity; arthritis; Treg dysfunction; leukocytoclastic vasculitis
Penetrance for gene: FGL2 were set to unknown
Review for gene: FGL2 was set to RED
Added comment: One subject from one kindred with homozygous truncating FGL2 variant. Some in vitro phenotype rescue and mouse model.
Sources: Literature
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 v4.51 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 v4.50 MAN2B2 Hannah Knight reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35637269; Phenotypes: Severe developmental delay, dysmorphic facial features, immune dysregulation, developmental delay, stroke; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 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 v4.39 CR2 Achchuthan Shanmugasundram Phenotypes for gene: CR2 were changed from Immunodeficiency, common variable, 7, 614699; Lupus; Immunodeficiency, common variable, 7; Common variable immunodeficiency disorders (CVID); Isolated IgG subclass deficiency; hypogammaglobulinaemia; Recurrent infections; Predominantly Antibody Deficiencies to ?Immunodeficiency, common variable, 7, OMIM:614699
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 v4.37 TLR7 Arina Puzriakova edited their review of gene: TLR7: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed 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 v4.35 JAK1 Hannah Knight changed review comment from: Now four families reported, and variants seem to cluster.
PMID: 28111307 - mother and two sons with immune disorder. De novo variant in mother, also in both children (p.A634D)
PMID: 32750333 - early-onset multi-organ immune dysregulation resulting from a mosaic variant not found in either parent (p.S703I)
PMID: 34496019 - somatic variant found in a patient with hypereosinophilia (p.R629_S632delinsSA)
PMID: 35046931 - novel variant (p.H596D) in an individual with a unique autoinflammatory keratinization disease

Also one report of biallelic disease in 2016 (PMID: 28008925), but none others since then; to: Now four families reported, and variants seem to cluster.
PMID: 28111307 - mother and two sons with immune disorder. De novo variant in mother, also in both children (p.A634D)
PMID: 32750333 - early-onset multi-organ immune dysregulation resulting from a mosaic variant not found in either parent (p.S703I)
PMID: 34496019 - somatic variant found in a patient with hypereosinophilia (p.R629_S632delinsSA)
PMID: 35046931 - novel variant (p.H596D) in an individual with a unique autoinflammatory keratinization disease

Also one report of biallelic disease in 2016 (PMID: 28008925), but none others since then
Primary immunodeficiency or monogenic inflammatory bowel disease v4.35 JAK1 Hannah Knight reviewed gene: JAK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28111307, 32750333, 34496019, 35046931; Phenotypes: Autoinflammation, immune dysregulation, and eosinophilia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.28 DOCK11 Achchuthan Shanmugasundram Phenotypes for gene: DOCK11 were changed from early-onset autoimmunity; cytopenia; systemic lupus erythematosus; dermatitis; enteropathy to Autoinflammatory disease, multisystem, with immune dysregulation, X-linked, OMIM:301109
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 DOCK11 Achchuthan Shanmugasundram reviewed gene: DOCK11: Rating: GREEN; Mode of pathogenicity: None; Publications: 36952639, 37342957; Phenotypes: Autoinflammatory disease, multisystem, with immune dysregulation, X-linked, OMIM:301109; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
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 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 v4.21 TLR7 Achchuthan Shanmugasundram Mode of inheritance for gene: TLR7 was changed 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 v4.5 C2orf69 Arina Puzriakova Phenotypes for gene: C2orf69 were changed from hypomyelination; microcephaly; liver dysfunction; autoinflammation; leukoencephalopathy to Combined oxidative phosphorylation deficiency 53, OMIM:619423
Primary immunodeficiency or monogenic inflammatory bowel disease v3.7 TBX1 Arina Puzriakova Phenotypes for gene: TBX1 were changed from Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability; Di George syndrome; Severe combined immunodeficiency (SCID); DiGeorge syndrome 188400; T-B+ SCID; Combined immunodeficiencies with associated or syndromic features to DiGeorge syndrome, OMIM:188400; Conotruncal anomaly face syndrome, OMIM:217095; Velocardiofacial syndrome, OMIM:192430
Primary immunodeficiency or monogenic inflammatory bowel disease v3.2 STAT5B Arina Puzriakova Phenotypes for gene: STAT5B were changed from Growth hormone insensitivity with immunodeficiency 245590; T-B+ SCID; Combined immunodeficiency; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Combined immunodeficiencies with associated or syndromic features to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, OMIM:618985; T-B+ SCID; Combined immunodeficiency; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Combined immunodeficiencies with associated or syndromic features
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 v2.581 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
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 v2.578 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; 618213; Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM; TGFB1 deficiency; Diseases of Immune Dysregulation; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 LYN Boaz Palterer gene: LYN was added
gene: LYN was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LYN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LYN were set to 36122175
Phenotypes for gene: LYN were set to Autoinflammatory; Neutrophilic vasculitis; Liver fibrosis; Chronic urticaria; Atopic dermatitis; Fever
Penetrance for gene: LYN were set to unknown
Review for gene: LYN was set to GREEN
Added comment: Louvrier et al. described 1 patient ( PMID 36122175 ) and De Jesus et al ( https://www.medrxiv.org/content/10.1101/2022.09.27.22280319v1.full.pdf ) 3 additional patients, for a total of 4 kindreds with de novo LYN mutations.
Strong functional evidence: p.Tyr508His, p.Tyr508Phe and p.Tyr508* cause inhibition loss, leading to Tyr397 autophosphorylation and functional GOF.
Sources: Literature
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 v2.573 TPP2 Eleanor Williams Phenotypes for gene: TPP2 were changed from Tripeptidyl-Peptidase II Deficiency; TPP2 deficiency; Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome; immune thrombocytopenia and autoimmune hemolytic anemia; Evans syndrome; Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections; Diseases of Immune Dysregulation to Tripeptidyl-Peptidase II Deficiency; TPP2 deficiency; Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome; immune thrombocytopenia and autoimmune hemolytic anemia; Evans syndrome; Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections; Diseases of Immune Dysregulation; Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
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 v2.563 TLR8 Arina Puzriakova Mode of inheritance for gene: TLR8 was changed from Unknown 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 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 v2.557 ATAD3A Boaz Palterer gene: ATAD3A was added
gene: ATAD3A was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 34387651
Phenotypes for gene: ATAD3A were set to Developmental delay; Hypotonia; Dystonia; Systemic sclerosis; Autoimmunity; Contractures; Basal ganglia calcifications; Interferonopathy
Penetrance for gene: ATAD3A were set to unknown
Review for gene: ATAD3A was set to GREEN
Added comment: Leppeley et al. described 8 patients across 7 kindreds (one inherited and 7 de novo), with mono or biallelic variants in ATAD3A. Patients presented with a wide clinical spectrum and all presented elevated IFN signature.
Functional data provided: "Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA."
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.557 SASH3 Sarah Leigh Phenotypes for gene: SASH3 were changed from Combined immunodeficiency; lymphopenia; neutropenia; immunodysregulation; autoimmune cytopenias to Immunodeficiency 102, OMIM:301082
Primary immunodeficiency or monogenic inflammatory bowel disease v2.543 FASLG Eleanor Williams Phenotypes for gene: FASLG were changed from Autoimmune lymphoproliferative syndrome, type IB, 601859; Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG); Autoimmune lymphoproliferative syndrome (ALPS); Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated; Diseases of Immune Dysregulation to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; autoimmune lymphoproliferative syndrome type 1, MONDO:0011158; SLE
Primary immunodeficiency or monogenic inflammatory bowel disease v2.526 CRACR2A Zornitza Stark gene: CRACR2A was added
gene: CRACR2A was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CRACR2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRACR2A were set to PMID:34908525
Phenotypes for gene: CRACR2A were set to late onset combined immunodeficiency
Review for gene: CRACR2A was set to RED
Added comment: PMID:34908525 - one patient compound het (missense and PTC) with late onset combined immunodeficiency (current chest infections, panhypogammaglobulinemia and CD4+T cell lymphopenia). Functional studies showed defective JNK phosphorylation, defective SOCE and impaired cytokine production.
Sources: Literature
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 v2.523 CARD14 Arina Puzriakova Phenotypes for gene: CARD14 were changed from CARD14 mediated psoriasis; Psoriasis 2, 602723; Pityriasis rubra pilaris,173200; Other autoinflammatory diseases with known genetic defect; Psoriasis; Autoinflammatory Disorders; immune dysregulation to Pityriasis rubra pilaris, OMIM:173200; Psoriasis 2, OMIM:602723; Autoinflammatory Disorders
Primary immunodeficiency or monogenic inflammatory bowel disease v2.515 PLCG2 Arina Puzriakova Phenotypes for gene: PLCG2 were changed from Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614878; Familial cold autoinflammatory syndrome 3 614468; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory; Familial cold autoinflammatory syndrome 3; Other autoinflammatory diseases with known genetic defect; Cold urticaria hypogammaglobulinemia, autoinflammation; Autoinflammatory Disorders to Autoinflammation, antibody deficiency, and immune dysregulation syndrome, OMIM:614878; Familial cold autoinflammatory syndrome 3, OMIM:614468; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 IKZF2 Boaz Palterer gene: IKZF2 was added
gene: IKZF2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IKZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IKZF2 were set to 34826260
Phenotypes for gene: IKZF2 were set to combined immunodeficiency; thrush; mucosal ulcers; chronic lymphoadenopathy; reduced MAIT cells
Penetrance for gene: IKZF2 were set to unknown
Added comment: Patients carrying the IKZF2 variant presented with a combined immunodeficiency phenotype characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, and chronic lymphadenopathy. Reduced Helios expression was associated with chronic T cell activation and increased production of proinflammatory cytokines both in effector and regulatory T cells.
Sources: Literature
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 v2.486 DEF6 Arina Puzriakova Phenotypes for gene: DEF6 were changed from DEF6 deficiency; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections; Diseases of Immune Dysregulation to Immunodeficiency 87 and autoimmunity, OMIM:619573; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities, 617425; EXTL3 deficiency; Platyspondyly, kyphosis, variable skeletal dysplasias, developmental delay; Combined immunodeficiencies with associated or syndromic features to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
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 v2.467 KDM6A Arina Puzriakova Phenotypes for gene: KDM6A were changed from Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Kabuki Syndrome 2 due to KDM6A deficiency; Combined immunodeficiencies with associated or syndromic features to Kabuki syndrome 2, OMIM:300867; Recurrent infections (otitis media, pneumonia); Autoimmunity; Combined immunodeficiencies with associated or syndromic features
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 v2.463 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, 147920; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features to Kabuki syndrome 1, OMIM:147920; Hypogammaglobulinemia; Recurrent infections (otitis media, pneumonia); Autoimmunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.462 ELF4 Arina Puzriakova Phenotypes for gene: ELF4 were changed from X-linked hypogammaglobulinemia with isolated growth hormone deficiency to Inflammatory bowel disease; Mucosal inflammation; Fever; Ulcers; Behcet-like disease; X-linked hypogammaglobulinemia with isolated growth hormone deficiency
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 v2.458 KDM6A Dmitrijs Rots reviewed gene: KDM6A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34326534; Phenotypes: Autoinflammatory, inflammatory bowel disease, ulcers; 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 v2.454 RGS10 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single family with 3 affected sibs reported (PMID:34315806), who presented with short stature and immunodeficiency and harboured compound het variants in RGS10 that segregated with disease. However, the sibs also carried a heterozygous PIK3CD (E525K) variant that has previously been deemed pathogenic in Activated PI3 Kinase Delta Syndrome (APDS), a primary immunodeficiency. The variant was excluded as the father also carried the PIK3CD variant but was mostly healthy and none of the 3 affected sibs displayed the full spectrum of symptoms associated with APDS. Nonetheless, APDS is a clinically heterogeneous condition with variable penetrance among affected individuals and so the contribution of PIK3CD to the patients immune dysregulation cannot be completely ruled out.

There are no further reports of an association between RGS10 variants and immunodeficiency to date, and therefore rating Red until further evidence emerges.
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 v2.444 IPO8 Ivone Leong Added comment: Comment on list classification: New gene added by Boaz Palterer (University of Florence). This gene is associated with a phenotype in Gene2Phenotype but not OMIM. As immune dysregulation is not seen in all affected individuals (PMID:34010604) and PMID:34010605 did not investigate the immune status of their cohort this gene has been given an Amber rating until further cases are available.
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 v2.434 IPO8 Ivone Leong Added comment: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients. The study also describes a knockout mouse model which recapitulates the human phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.427 SASH3 Zornitza Stark reviewed gene: SASH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33876203; Phenotypes: Combined immunodeficiency, immune dysregulation; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
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 v2.424 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 CSF2 Boaz Palterer gene: CSF2 was added
gene: CSF2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CSF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSF2 were set to 33349924
Phenotypes for gene: CSF2 were set to Behcet-like disease; Pathergy
Penetrance for gene: CSF2 were set to unknown
Mode of pathogenicity for gene: CSF2 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: CSF2 was set to RED
Added comment: Rösler et al. described a kindred with two patients affected by a Behcet-like disease characterized by marked pathergy and absent inflammation. They identified a heterozygous variant in the GM-CSF gene CSF2 (c.130A>C, p.N44H) resulting in disruption of an N-glycosylation site. They show that de-glycosylated GM-CSF enhances STAT-5 phosphorylation, and therefore the variant acts as a gain-of-function.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 LRRC32 Boaz Palterer gene: LRRC32 was added
gene: LRRC32 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to Unknown
Publications for gene: LRRC32 were set to 34059789
Phenotypes for gene: LRRC32 were set to Common variable immunodeficiency; Enteropathy; Lymphopenia; Reduced Tregs
Penetrance for gene: LRRC32 were set to unknown
Review for gene: LRRC32 was set to RED
Added comment: Lehmkuhl et al. described two patients with immune dysregulation and mutations of LRRC32. Both patients carried two rare variants, however, patient 1 has both variants in cis, while patient 2 was a compound heterozygote. Reduced protein expression ex-vivo was demonstrated. Conditional mice KO model recapitulated the phenotype.
Sources: Literature
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 STXBP3 Zornitza Stark reviewed gene: STXBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33891011; Phenotypes: Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss, Immune Dysregulation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
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 v2.414 SYK Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - PMID:33782605 report distinct monoallelic GoF variants in 5 families (6 individuals) with immune dysregulation and inflammation. Expression of one of these variants in a mouse model replicated aspects of the human immunopathology.
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 v2.413 SYK Zornitza Stark reviewed gene: SYK: Rating: GREEN; Mode of pathogenicity: None; Publications: 33782605; Phenotypes: Immune dysregulation and systemic inflammation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 MPEG1 Zornitza Stark gene: MPEG1 was added
gene: MPEG1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754
Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223
Review for gene: MPEG1 was set to GREEN
gene: MPEG1 was marked as current diagnostic
Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus.

Four individuals reported, functional data, including animal model.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.412 PRIM1 Arina Puzriakova gene: PRIM1 was added
gene: PRIM1 was added to Primary immunodeficiency. Sources: Literature
Q2_21_rating tags were added to gene: PRIM1.
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to GREEN
Added comment: PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype.

- PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
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 v2.410 ARPC1B Arina Puzriakova Phenotypes for gene: ARPC1B were changed from Thrombocytopenia & Immune Deficiency; Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718; inflammatory predisposition; Immunodeficiency with thrombocytopenia; Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching; Combined immunodeficiencies with associated or syndromic features to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718; Combined immune deficiency with or without thrombocytopenia; Inflammatory predisposition
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 v2.392 RHOG Boaz Palterer gene: RHOG was added
gene: RHOG was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RHOG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHOG were set to 33513601
Phenotypes for gene: RHOG were set to HLH; hemophagocytic lymphohistiocytosis
Penetrance for gene: RHOG were set to unknown
Review for gene: RHOG was set to RED
Added comment: One patient with HLH and impaired cytotoxic T lymphocyte and natural killer (NK) cell exocytosis functions, bearing biallelic deleterious mutations in the RhoG gene.
Experimental ablation of RHOG in a model cell line and primary CTLs confirmed that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for cytotoxic granules fusion with the plasma membrane.
Sources: Literature
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 v2.392 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, 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.; 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; no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.391 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 v2.386 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LCP2 Boaz Palterer gene: LCP2 was added
gene: LCP2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LCP2 were set to 33231617
Phenotypes for gene: LCP2 were set to SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation
Penetrance for gene: LCP2 were set to unknown
Review for gene: LCP2 was set to AMBER
Added comment: One patient with severe combined immunodeficiency was found to have biallelic mutations in SLP76.
Sources: Literature
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 UBA1 Zornitza Stark gene: UBA1 was added
gene: UBA1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: UBA1 was set to Other
Publications for gene: UBA1 were set to 33108101
Phenotypes for gene: UBA1 were set to Autoinflammatory disease, adult onset; VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
Review for gene: UBA1 was set to GREEN
Added comment: 25 men reported with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation, and an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopaenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis.
Sources: Literature
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 v2.369 FAAP24 Eleanor Williams edited their review of gene: FAAP24: Added comment: Not associated with a phenotype in OMIM.

PMID: 17289582 - Ciccia et al 2007 - report that FAAP24 (C19ORF40) is a component of the Fanconi anemia (FA) core complex and interacts with the C-terminal region of FANCM. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage.

PMID: 27473539 - Daschkey et al 2016 - report a homozygous missense mutation in FAAP24 (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.; Changed rating: RED; Changed phenotypes: EBV-associated lymphoproliferative disease; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 AP3D1 Eleanor Williams edited their review of gene: AP3D1: Added comment: Provisionally associated with Hermansky-Pudlak syndrome 10 #617050 (AR) in OMIM.

PMID: 30472485 - Mohammad et al 2019 - 1 family with parents who were first cousins with three affected children who presented similarly with severe seizures, developmental delay, albinism, and immunodeficiency. Whole exome sequencing identified homozygosity for AP3D1 deleterious sequence variant (NM_001261826.3:c.1978delG: p.Ala660Argfs*54) which co-segregated with the phenotype. The variant is not found in the gnomAD database or in an in-house database of 284 exome or Middle Eastern population specific database.

PMID: 26744459 - Ammann et al 2016 - report a patient with consanguineous Turkish parents presenting with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing. Whole exome sequencing identified a homozygous mutation in AP3D1 (c.3565_3566delGT) that leads to destabilization of the adaptor protein 3 (AP3) complex.; Changed rating: AMBER; Changed phenotypes: Hermansky-Pudlak syndrome 10, 617050; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.269 LAT Eleanor Williams Classified gene: LAT as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.269 LAT Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.269 LAT Eleanor Williams Gene: lat has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 LAT Eleanor Williams Source Other was added to LAT.
Publications for gene LAT were updated from 27522155; 27242165 to 27522155; 27242165
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 ZAP70 Eleanor Williams edited their review of gene: ZAP70: Added comment: The following PubMed IDs were added to gene ZAP70 (OMIM gene MIM#176947): 19548248;18509675;8202713;26783323;25805655;25732729. These publications have been associated with the gene by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 19548248, 18509675, 8202713, 26783323, 25805655, 25732729
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 XIAP Eleanor Williams edited their review of gene: XIAP: Added comment: The following PubMed IDs were added to entity XIAP: 31754776;23973892;21119115;26581487;23131490. These publications have been associated with OMIM phenotype MIM#300635, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 31754776, 23973892, 21119115, 26581487, 23131490
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STAT3 Eleanor Williams edited their review of gene: STAT3: Added comment: The following PubMed IDs were added to entity STAT3: 25349174;28402852;25359994;25038750. These publications have been associated with OMIM phenotype MIM#615952, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 25349174, 28402852, 25359994, 25038750
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 SH2D1A Eleanor Williams edited their review of gene: SH2D1A: Added comment: The following PubMed IDs were added to entity SH2D1A: 31754776;21119115;25085526. These publications have been associated with OMIM phenotype MIM#308240, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 31754776, 21119115, 25085526
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 PRKCD Eleanor Williams edited their review of gene: PRKCD: Added comment: The following PubMed IDs were added to gene PRKCD (OMIM gene MIM#176977): 27541826;23666743;23319571. These publications have been associated with the gene by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 27541826, 23666743, 23319571
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 LAT Eleanor Williams reviewed gene: LAT: Rating: ; Mode of pathogenicity: ; Publications: 27522155; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.195 MAGT1 Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853 to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 300853; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation
Primary immunodeficiency or monogenic inflammatory bowel disease v2.194 MAGT1 Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853
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 v2.187 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 v2.184 TET2 Zornitza Stark reviewed gene: TET2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32518946; Phenotypes: Immune dysregulation, Lymphoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
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 v2.175 NCKAP1L Zornitza Stark gene: NCKAP1L was added
gene: NCKAP1L was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: NCKAP1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCKAP1L were set to 32647003
Phenotypes for gene: NCKAP1L were set to Immunodeficiency; Immune dysregulation
gene: NCKAP1L was marked as current diagnostic
Added comment: 5 individuals from 4 families with recurrent bacterial and viral skin infections, severe respiratory tract infections leading to pneumonia and bronchiectasis. Functional studies of the 4 missense reported were performed.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. The immune dysfunction phenotype is not as clear as the platelet anomalies and ocular / oculocutaneous albinism phenotype. Therefore rating this gene as amber for now.
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 v2.162 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 v2.160 IL6R Sarah Leigh Phenotypes for gene: IL6R were changed from Hyper-IgE; Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features to [Interleukin 6, serum level of, QTL] 614752; [Interleukin-6 receptor, soluble, serum level of, QTL] 614689; Hyper-IgE; Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features
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 v2.145 NOS2 Ivone Leong Added comment: Comment on list classification: Gene was added to panel by Zornitza Stark (Australian Genomics). The gene was given the suggested Red rating based on evidence provided by expert reviewer.

PMID: 31995689 describes a 51 year old man from Iran who had an acute cytomegalovirus (CMV) infection which progressed to CMV disease and later died from it. The researchers found a homozygous variant that causes a frameshift mutation in NOS2 that caused NOS2 deficiency, which might cause the patient to be more susceptible to lethal CMV infection. The patient was otherwise healthy until the CMV infection.
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 v2.139 PIK3CG Zornitza Stark gene: PIK3CG was added
gene: PIK3CG was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PIK3CG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3CG were set to 32001535; 31554793
Phenotypes for gene: PIK3CG were set to Immune dysregulation; HLH-like; childhood-onset antibody defects; cytopenias; T lymphocytic pneumonitis and colitis
Review for gene: PIK3CG was set to GREEN
Added comment: Two individuals with complex immunological phenotypes reported and a mouse model.
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 v2.124 BLOC1S6 Eleanor Williams changed review comment from: Provisionally associated with ?Hermansky-pudlak syndrome 9 #614171 (AR) in OMIM.
BLOC1S6 is also known as PLDN and HPS9.

PMID: 32245340 - Michaud et al 2020 - report 1 patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. (Abstract only accessed).

PMID: 22461475 - Badolato et al 2012 - report a northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. She had thrombocytopenia and leukopenia, with normal platelet aggregation. WES found a homozygous nonsense mutation, c.232C > T (p.Q78X) in PLDN (BLOC1S6). This variant was confirmed homozygous in the patient and heterozygous in her parents by Sanger sequencing, and was associated with absent PLDN protein expression

PMID: 26575419 - Yousaf et al 2016 - report a Pakistani family in which the proband had a nonsense mutation is the HPS9/PLDN gene (c.232C>T, p.Gln78*). The 4-year-old female patient reported here, had Oculocutaneous albinism, photophobia, nystagmus, prolonged bleeding and clotting times, which indicate platelet dysfunction.

PMID: 21665000 - Cullinane et al 2011 - RETRACTED PAPER - report 1 9-month old male patient of Indian ancestry with a homozygous c.232C>T; p.Gln78Och mutation and HPS-like phenotype. This paper has been retracted due to falsified and/or fabricated gel images which represent expression of PLDN in fibroblasts and melanocytes.

Summary: 3 reports + retracted paper. 2 out of the 3 patients had abnormal platelet aggregation.; to: Provisionally associated with ?Hermansky-pudlak syndrome 9 #614171 (AR) in OMIM.
BLOC1S6 is also known as PLDN and HPS9.

PMID: 32245340 - Michaud et al 2020 - report 1 patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. (Abstract only accessed).

PMID: 22461475 - Badolato et al 2012 - report a northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. She had thrombocytopenia and leukopenia, with normal platelet aggregation. WES found a homozygous nonsense mutation, c.232C > T (p.Q78X) in PLDN (BLOC1S6). This variant was confirmed homozygous in the patient and heterozygous in her parents by Sanger sequencing, and was associated with absent PLDN protein expression

PMID: 26575419 - Yousaf et al 2016 - report a Pakistani family in which the proband had a nonsense mutation is the HPS9/PLDN gene (c.232C>T, p.Gln78*). The 4-year-old female patient reported here, had Oculocutaneous albinism, photophobia, nystagmus, prolonged bleeding and clotting times, which indicate platelet dysfunction.

PMID: 21665000 - Cullinane et al 2011 - RETRACTED PAPER - report 1 9-month old male patient of Indian ancestry with a homozygous c.232C>T; p.Gln78Och mutation and HPS-like phenotype. This paper has been retracted due to falsified and/or fabricated gel images which represent expression of PLDN in fibroblasts and melanocytes.

Summary: 3 reports + retracted paper. 2 out of the 3 patients had abnormal platelet aggregation. The 3rd had thrombocytopenia and leukopenia, with normal platelet aggregation.
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 v2.87 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 v2.86 IRF4 Zornitza Stark gene: IRF4 was added
gene: IRF4 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: IRF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF4 were set to 29537367
Phenotypes for gene: IRF4 were set to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724
Review for gene: IRF4 was set to RED
Added comment: Single family reported with Whipple's disease and a rare missense in IRF4. Younger healthy carrier members of the family had the same variant as older affected individuals, leading the authors to speculate about age-dependent penetrance. GWAS indicates separate link with skin/hair/eye pigmentation.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.71 TRIM22 Ivone Leong Phenotypes for gene: TRIM22 were changed from Autoinflammatory Disorders; Granulomatous colitis; Diseases of Immune Dysregulation; TRIM22 to Autoinflammatory Disorders; Granulomatous colitis; Diseases of Immune Dysregulation; TRIM22; Inflammatory bowel disease
Primary immunodeficiency or monogenic inflammatory bowel disease v2.57 RC3H1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited 01/27/2017) or in Gen2Phen. PMID 31636267 reports a biallelic nonsense variant (p.R688*), in a case with immune dysregulation syndrome
characterized by severe hyperinflammation in a consanguineous family. The association of this variant with the phenotype is supported by functional studies and mouse model (PMID 15917799).
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 IL6R Zornitza Stark reviewed gene: IL6R: Rating: AMBER; Mode of pathogenicity: None; Publications: 31235509; Phenotypes: Recurrent pyogenic infections, cold abscesses, High circulating IL-6 levels, High IgE; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 FCHO1 Zornitza Stark reviewed gene: FCHO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32098969, 30822429; Phenotypes: Combined immunodeficiency, T cells: low, poor proliferation, B cells: normal number, Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, Failure to thrive, Increased activation-induced T-cell death, Defective clathrin-mediated endocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 ERBIN Zornitza Stark reviewed gene: ERBIN: Rating: AMBER; Mode of pathogenicity: None; Publications: 28126831; Phenotypes: Recurrent respiratory infections, Susceptibility to S.aureus, Eczema, Hyperextensible joints, Scoliosis, Arterial dilatation in some; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v2.45 IL6 Ellen McDonagh gene: IL6 was added
gene: IL6 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IL6 was set to Unknown
Publications for gene: IL6 were set to medRxiv 2020.04.01.20047381; doi: https://doi.org/10.1101/2020.04.01.20047381
Phenotypes for gene: IL6 were set to Potential marker for respiratory failure when infected with COVID-19
Review for gene: IL6 was set to RED
Added comment: Not yet peer-reviewed study available in medRxiv: https://www.medrxiv.org/content/10.1101/2020.04.01.20047381v1
reports an association between elevated interleukin-6 (IL-6) in COVID-19 infected patients with the need for mechanical ventilation (p=1.2.10-5). The maximal IL-6 level (cutoff 80 pg/ml) for each patient during disease predicted respiratory failure with high accuracy (p=1.7.10-8, AUC=0.98). The risk of respiratory failure for patients with IL-6 levels of ≥ 80 pg/ml was 22 times higher compared to patients with lower IL-6 levels.
Sources: Literature
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 v2.40 IFNAR1 Sarah Leigh gene: IFNAR1 was added
gene: IFNAR1 was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: IFNAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFNAR1 were set to 31270247; 26676772; 20020050
Phenotypes for gene: IFNAR1 were set to IFNAR1 associated adverse reactions to certain live attenuated viral vaccines
Review for gene: IFNAR1 was set to AMBER
Added comment: Hypothesis from Abdelazeem Elhabyan (Tanta University Hospitals): this gene is involved in the interferon-mediated immune response to viruses of those is SARS Coronavirus (2003) which down-regulates the IFNAR1 receptors through its 3a protein. Additionally, Influenzavirus A suppress immune response by downregulation of this gene. It has been also linked to adverse reactions to measles and yellow fever vaccines in healthy individuals.
Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.38 IRF9 Catherine Snow gene: IRF9 was added
gene: IRF9 was added to Primary immunodeficiency. Sources: Expert Review
Mode of inheritance for gene: IRF9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IRF9 were set to 30143481; 30826365
Phenotypes for gene: IRF9 were set to Immunodeficiency 65, susceptibility to viral infections, 618648
Review for gene: IRF9 was set to AMBER
Added comment: Identified by external reviewer as not present in the Primary immunodeficiency (version 2.37) or the research Viral susceptibility panel (version 0.35).

PMID:30143481 - Life-threatening Influenza Pneumonitis in a Child With Inherited IRF9 Deficiency. 5 year old Algerian girl homozygous for LOF variant c.991G>A and was hospitalized for severe infection with IAV requiring mechanical ventilation and Tamiflu treatment, and who had a history of recurrent benign bronchiolitis, biliary perforation following measles-mumps-rubella (MMR) vaccination at 1 yr of age, and recurrent fevers without a causative pathogen identified.

PMID:30826365 - identifies a homozygous splicing mutation in the IRF9 gene in a family of Portugese origin. The variant, c.577+1G>T (NM_006084), which is located in the donor splice site of introns 5 and 6. The proband is was a 10-year-old boy born at term to healthy consanguineous parents (first cousins of Portuguese origin and residents of Venezuela). From the first year of life, the child displayed a marked susceptibility to viral infections with moderate-to-severe symptoms of disease that resulted in persistent neurological impairment and bronchiectasis. A six month old sibling who has the same homozygous variant has had preventative treatment with IVIG and cotrimoxazole and has not presented with infections.

PMID: 28878077 - During early viral infection, overwhelming antigen exposure can cause functional exhaustion of CD8+ T cells and lead to chronic infection this paper reports on a mouse study which demonstrates that IRF9 plays a role in preventing CD8+ T cell exhaustion.
Sources: Expert Review
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 v2.34 WRAP53 Louise Daugherty Source IUIS Classification December 2019 was added to WRAP53.
Mode of inheritance for gene WRAP53 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure for gene: WRAP53
Publications for gene WRAP53 were updated from to 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 TERC Louise Daugherty Source IUIS Classification December 2019 was added to TERC.
Added phenotypes Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure for gene: TERC
Publications for gene TERC were updated from 16332973; 11574891; 12525685 to 32048120; 12525685; 16332973; 11574891; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 TBX1 Louise Daugherty Source IUIS Classification December 2019 was added to TBX1.
Added phenotypes Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability; Combined immunodeficiencies with associated or syndromic features for gene: TBX1
Publications for gene TBX1 were updated from 24198816; 14585638; 11242110 to 11242110; 14585638; 24198816; 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 NFAT5 Louise Daugherty Source IUIS Classification December 2019 was added to NFAT5.
Added phenotypes IBD, recurrent sinopulmonary infections; Diseases of Immune Dysregulation for gene: NFAT5
Publications for gene NFAT5 were updated from to 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 KMT2D Louise Daugherty Source IUIS Classification December 2019 was added to KMT2D.
Added phenotypes Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features for gene: KMT2D
Publications for gene KMT2D were updated from 15887282; 25142838; 15523604; 26411453 to 25142838; 32048120; 15887282; 15523604; 26411453; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 KDM6A Louise Daugherty Source IUIS Classification December 2019 was added to KDM6A.
Added phenotypes Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features for gene: KDM6A
Publications for gene KDM6A were updated from 26411453; 25546742; 15887282; 25142838; 15523604 to 25546742; 25142838; 32048120; 15887282; 15523604; 26411453; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 JAK1 Louise Daugherty Source IUIS Classification December 2019 was added to JAK1.
Mode of inheritance for gene JAK1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Diseases of Immune Dysregulation; HSM, eosinophilic enteritis, thyroid disease, poor growth, viral infections for gene: JAK1
Publications for gene JAK1 were updated from 28111307 to 32048120; 28111307; 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 v2.34 IL6R Louise Daugherty Source IUIS Classification December 2019 was added to IL6R.
Added phenotypes Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features for gene: IL6R
Publications for gene IL6R were updated from 31235509 to 32048120; 31235509; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 FAAP24 Louise Daugherty Source IUIS Classification December 2019 was added to FAAP24.
Added phenotypes Diseases of Immune Dysregulation; EBV infection-driven lymphoproliferative disease for gene: FAAP24
Publications for gene FAAP24 were updated from 27473539 to 32048120; 27473539; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.33 TINF2 Louise Daugherty Phenotypes for gene: TINF2 were changed from DBone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay exudative retinopathy to Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay exudative retinopathy
Primary immunodeficiency or monogenic inflammatory bowel disease v2.32 TINF2 Louise Daugherty Phenotypes for gene: TINF2 were changed from Dyskeratosis congenita 3; Dyskeratosis congenita; Hoyeraal-Hreidarsson syndrome; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; Combined immunodeficiencies with associated or syndromic features to DBone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay exudative retinopathy
Primary immunodeficiency or monogenic inflammatory bowel disease v2.31 TERT Louise Daugherty Phenotypes for gene: TERT were changed from Dyskeratosis congenita 2 613989, Dyskeratosis congenita 4 613989; Dyskeratosis congenita; Hoyeraal-Hreidarsson syndrome; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; Combined immunodeficiencies with associated or syndromic features to Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure
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 v2.28 TINF2 Louise Daugherty commented on gene: TINF2: OriginaI Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): TINF2. PanelApp HGNC gene symbol check: TINF2 . IUIS Disease: AD-DKC due to TINF2 deficiency . IUIS Inheritance: AD .T cells: normal to low / normal to low .B cells: normal to low / normal to low, .IUIS Other affected cells: Hematopoietic stem cell / Hematopoietic stem cell. IUIS Associated features: Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay. IUIS Major category: Bone marrow failure IUIS Subcategory: none given
Primary immunodeficiency or monogenic inflammatory bowel disease v2.28 TERT Louise Daugherty commented on gene: TERT: OriginaI Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): TERT .PanelApp HGNC gene symbol check: TERT . IUIS Disease: AD/AR-DKC due to TERT deficiency . IUIS Inheritance: AD or AR .T cells: normal to low / normal to low, .B cells: Normal to low / normal to low, .IUIS Other affected cells: Hematopoietic stem cell / Hematopoietic stem cell. IUIS Associated features: Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay / Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay. IUIS Major category: Bone marrow failure, UIS Subcategory: none given
Primary immunodeficiency or monogenic inflammatory bowel disease v2.27 CFB Louise Daugherty changed review comment from: OriginaI Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): CFB .PanelApp HGNC gene symbol check: CFB . IUIS Disease: Factor B . IUIS Inheritance: AD .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Atypical Hemolytic-uremic syndrome. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A. // OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CFB .PanelApp HGNC gene symbol check: CFB . IUIS Disease: Factor B . IUIS Inheritance: AD GOF / AR .T cells: Normal / Normal , .B cells: Normal / Normal, Immunoglobulin levels:Normal / Normal, Neutrophil count: Normal / Normal .IUIS Other affected cells: N/A. IUIS Associated features: Infections with encapsulated organisms. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A.; to: OriginaI Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): CFB .PanelApp HGNC gene symbol check: CFB . IUIS Disease: Factor B . IUIS Inheritance: AD .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Atypical Hemolytic-uremic syndrome. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A. // OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CFB .PanelApp HGNC gene symbol check: CFB . IUIS Disease: Factor B . IUIS Inheritance: AD GOF / AR .T cells: Normal / Normal , .B cells: Normal / Normal, Immunoglobulin levels:Normal / Normal, Neutrophil count: Normal / Normal .IUIS Other affected cells: N/A. IUIS Associated features: Infections with encapsulated organisms. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.27 CFB Louise Daugherty commented on gene: CFB: OriginaI Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): CFB .PanelApp HGNC gene symbol check: CFB . IUIS Disease: Factor B . IUIS Inheritance: AD .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Atypical Hemolytic-uremic syndrome. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A. // OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CFB .PanelApp HGNC gene symbol check: CFB . IUIS Disease: Factor B . IUIS Inheritance: AD GOF / AR .T cells: Normal / Normal , .B cells: Normal / Normal, Immunoglobulin levels:Normal / Normal, Neutrophil count: Normal / Normal .IUIS Other affected cells: N/A. IUIS Associated features: Infections with encapsulated organisms. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.17 DEF6 Louise Daugherty Phenotypes for gene: DEF6 were changed from to DEF6 deficiency; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections; Diseases of Immune Dysregulation
Primary immunodeficiency or monogenic inflammatory bowel disease v2.14 TGFB1 Louise Daugherty gene: TGFB1 was added
gene: TGFB1 was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: TGFB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TGFB1 were set to 32048120; 32086639
Phenotypes for gene: TGFB1 were set to Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; Diseases of Immune Dysregulation; TGFB1 deficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.14 FCHO1 Louise Daugherty gene: FCHO1 was added
gene: FCHO1 was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FCHO1 were set to 32048120; 32086639
Phenotypes for gene: FCHO1 were set to Recurrent infections, lymphoproliferation, increased activation-induced T-cell death, defective clathrin-mediated endocytosis; FCHO1 deficiency; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.13 FERMT1 Louise Daugherty gene: FERMT1 was added
gene: FERMT1 was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: FERMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FERMT1 were set to 32048120; 32086639
Phenotypes for gene: FERMT1 were set to Kindler syndrome, 173650; FERMT1 deficiency (Kindler syndrome); Diseases of Immune Dysregulation; Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling
Primary immunodeficiency or monogenic inflammatory bowel disease v2.13 TRIM22 Louise Daugherty gene: TRIM22 was added
gene: TRIM22 was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: TRIM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM22 were set to 32048120; 32086639
Phenotypes for gene: TRIM22 were set to Autoinflammatory Disorders; Granulomatous colitis; Diseases of Immune Dysregulation; TRIM22
Primary immunodeficiency or monogenic inflammatory bowel disease v2.11 ERBIN Louise Daugherty gene: ERBIN was added
gene: ERBIN was added to Primary immunodeficiency. Sources: IUIS Classification December 2019
Mode of inheritance for gene: ERBIN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ERBIN were set to 32086639; 32048120
Phenotypes for gene: ERBIN were set to ERBIN deficiency; Combined immunodeficiencies with associated or syndromic features; Recurrent respiratory infections, susceptibility to S. aureus, eczema, hyperextensible joints, scoliosis, arterial dilatation in some
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 v1.137 CSF2RA Louise Daugherty Mode of inheritance for gene: CSF2RA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v1.136 RASGRP1 Louise Daugherty Phenotypes for gene: RASGRP1 were changed from Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency; Immunodeficiency 64, 618534 to Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency; Immunodeficiency 64, 618534; Immunodeficiency; immunde dysregulation; EBV-induced lymphoma
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 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 MASP2 Louise Daugherty changed review comment from: Chronic infections due to MBL deficiency: 5% Europeans, 10% sub-saharan Africans, mostly unaffected. Increased risk of infections - is it useful clinically or if undergoing immunosuppression? Is it tested for clinically at present?; to: MASP2 deficiency: 4% caucasians, up to 18% of African populations - mostly asymptomatic. Is this a risk factor - is it useful in clinical practice? I don't know if this is a recurrent variant - may be too common?
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 v1.127 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 v1.103 BLOC1S6 Louise Daugherty gene: BLOC1S6 was added
gene: BLOC1S6 was added to Primary immunodeficiency. Sources: Other
Mode of inheritance for gene: BLOC1S6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BLOC1S6 were set to Hermansky-pudlak syndrome 9, 614171; HPS9, palladin deficiency (NK cell defect); Immune Dysregulation
Review for gene: BLOC1S6 was set to RED
Added comment: 2 reviews
Sophie Hambleton (Newcastle University)
[email protected]
Red List (low evidence)

Only 1 reported patient (a previous report had to be retracted).
Created: 19 Jun 2018, 5:47 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 19 Jun 2018, 5:47 a.m.

Panel version: 0.1006
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Your review
Louise Daugherty (Genomics England Curator)
[email protected]
I don't know

Comment on list classification: Changed from Amber to Red after external clinical review, only one bonafide case
Created: 20 Jun 2018, 3:10 p.m.

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After review decided to keep as Amber- currently there is only one case for HPS9 need more individuals to determine if immunodeficiency is a feature of BLOC-1 deficiency
Created: 11 May 2018, 4:31 p.m.

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Comment on publications: one one affected reported to date (2012). Added HPS gene review PMID: 20301464 (2017)
Created: 11 May 2018, 4:25 p.m.

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Comment on phenotypes: added PID phenotype
Created: 11 May 2018, 4:24 p.m.

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This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.
Created: 20 Apr 2018, 12:25 p.m.

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Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: BLOC1S6, GRID_Gene_Symbol: BLOC1S6, GRID_Transcript_ENS_Community submitted: ENST00000220531, GRID_Transcript_RefSeq: NM_012388.3, GRID_Transcript_ENS_used_on_Production: ENST00000220531
Created: 17 Apr 2018, 12:12 p.m.

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Created: 17 Apr 2018, 12:12 p.m.

Panel version: 0.679
Sources: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 LAT Louise Daugherty commented on gene: LAT: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 LAT Louise Daugherty commented on gene: LAT: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 LAT Kimberly Gilmour reviewed gene: LAT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 LAT Tracy Briggs reviewed gene: LAT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.88 RET Louise Daugherty Phenotypes for gene: RET were changed from to Central hypoventilation syndrome, congenital 209880
Primary immunodeficiency or monogenic inflammatory bowel disease v1.69 BLOC1S6 Louise Daugherty Phenotypes for gene: BLOC1S6 were changed from to Hermansky-pudlak syndrome 9, 614171; HPS9, palladin deficiency (NK cell defect); Immune Dysregulation
Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 LAT Louise Daugherty Source NHS GMS was added to LAT.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 LAT Louise Daugherty Source North West GLH was added to LAT.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 LAT Louise Daugherty Source London North GLH was added to LAT.
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 v1.52 RASGRP1 Louise Daugherty Phenotypes for gene: RASGRP1 were changed from Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency, to Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency; Immunodeficiency 64, 618534
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 v1.30 CFB Louise Daugherty Phenotypes for gene: CFB were changed from Complement factor B deficiency, 615561; Atypical Hemolytic-uremic syndrome; Infections with encapsulated organisms; Complement Deficiencies; Susceptibility to atypical haemolytic uraemic syndrome (4; AD); complement factor B deficiency (AR) to Complement factor B deficiency, 615561; Atypical Hemolytic-uremic syndrome; Infections with encapsulated organisms; Complement Deficiencies; Susceptibility to atypical haemolytic uraemic syndrome 4 (AD); complement factor B deficiency (AR)
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 v1.25 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 v1.19 CARD14 Louise Daugherty Phenotypes for gene: CARD14 were changed from CARD14 mediated psoriasis; Psoriasis 2, 602723; Pityriasis rubra pilaris,173200; Other autoinflammatory diseases with known genetic defect; Psoriasis; Autoinflammatory Disorders to CARD14 mediated psoriasis; Psoriasis 2, 602723; Pityriasis rubra pilaris,173200; Other autoinflammatory diseases with known genetic defect; Psoriasis; Autoinflammatory Disorders; immune dysregulation
Primary immunodeficiency or monogenic inflammatory bowel disease v1.17 FCGR3A Louise Daugherty commented on gene: FCGR3A: Additional external review added so this gene was reviewed again. Agree to keep this gene Amber until further evidence, especially noted high population frequency, including homozygotes in ExAC.
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 v1.12 RASGRP1 Louise Daugherty Phenotypes for gene: RASGRP1 were changed from Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation to Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency,
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 v1.8 ISCA-37433-Loss Louise Daugherty 22q11.2 recurrent (DGS/VCFS) region (proximal region, LCR22-A to -B) Loss was changed to 22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1) Loss
Added phenotypes 188400; immune deficiency; renal anomalies; 22q11.2 deletion syndrome; 192430; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; polyhydramnios; Velocardiofacial syndrome; Learning difficulties; diaphragmatic hernia; DiGeorge syndrome; congenital heart disease; cleft palate, polydactyly for Region: ISCA-37433-Loss
Publications for Region: ISCA-37433-Loss were changed from 15545748; 15889418; 20301696 to 15889418; 20301696; 15545748
Primary immunodeficiency or monogenic inflammatory bowel disease v1.6 ISCA-37433-Loss Louise Daugherty Region: ISCA-37433-Loss was added
Region: ISCA-37433-Loss was added to Primary immunodeficiency disorders. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Loss were set to 15545748; 15889418; 20301696
Phenotypes for Region: ISCA-37433-Loss were set to facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; diaphragmatic hernia; Learning difficulties; 192430; immune deficiency; congenital heart disease; 22q11.2 deletion syndrome; Velocardiofacial syndrome; DiGeorge syndrome; cleft palate, polydactyly; polyhydramnios; 188400; renal anomalies
Primary immunodeficiency or monogenic inflammatory bowel disease LAT Louise Daugherty edited their review of gene: LAT
Primary immunodeficiency or monogenic inflammatory bowel disease LAT Louise Daugherty classified LAT as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease LAT Louise Daugherty commented on gene: LAT
Primary immunodeficiency or monogenic inflammatory bowel disease LAT Sophie Hambleton reviewed gene: LAT
Primary immunodeficiency or monogenic inflammatory bowel disease LAT Louise Daugherty reviewed LAT
Primary immunodeficiency or monogenic inflammatory bowel disease LAT Louise Daugherty Added gene to panel