PMID: 25213377

Gene: CTLA4

HGNC: 2505

Disease: Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (also known as Autoimmune lymphoproliferative syndrome type V)

MONDO: 0014493

InheritancePattern: Autosomal Dominant

Prevalence: Estimated to be <1 in 1,000,000

Penetrance: More than 67% penetrant (PMID: 29729943), with childhood, adolescent, or adult onset

PMID: 25367873

Gene: CTLA4

HGNC: 2505

Disease: Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (also known as Autoimmune lymphoproliferative syndrome type V)

MONDO: 0014493

InheritancePattern: Autosomal Dominant

Prevalence: Estimated to be <1 in 1,000,000

Penetrance: More than 67% penetrant (PMID: 29729943), with childhood, adolescent, or adult onset

PMID: 27102614

Gene: CTLA4

HGNC: 2505

Disease: Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (also known as Autoimmune lymphoproliferative syndrome type V)

MONDO: 0014493

InheritancePattern: Autosomal Dominant

Prevalence: Estimated to be <1 in 1,000,000

Penetrance: More than 67% penetrant (PMID: 29729943), with childhood, adolescent, or adult onset

Case#: 2/M. 10 y.o. (onset) and 13 y.o. (at assessment), male

DiseaseAssertion: Patient had thrombocytopenia, associated bleeding, neutropenia, and lymphoid hyperplasia in lungs, lymph nodes, and brain, refractory to immunomodulatory therapy. The diagnosis of CTLA4 haploinsufficiency was made retrospectively in 7 patients who underwent HSCT for life-threatening, treatment-resistant immune dysregulation and in 1 patient prospectively (unclear which patients were identified retrospectively and prospectively).

FamilyInfo: None provided

CasePresentingHPOs: HP:0001873 (Thrombocytopenia), HP:0001875 (Neutropenia), OMIM:188030 (Immune thrombocytopenic purpura/ITP), HP:0001904 (Autoimmune neutropenia)

CaseHPOFreeText: ITP and autoimmune neutropenia, Reactive lymphoid hyperplasia—lymph nodes, lung, frontal lobe brain.

All 8 patients received steroids and a calcineurin inhibitor before transplant

Five patients (including this patient) had peripheral blood HSC grafts and received cyclosporine and mycophenolate mofetil (MMF) for graft versus host disease (GvHD) prophylaxis.

Patient died 4 months post-transplant due to transplant-related mortality of severe acute gut GvHD (Acute grade IV gut).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Not found

GenotypingMethod: Not found

PreviouslyPublished: Yes, Schwab et al. PMID: 29729943

Variant: NM_005214.5:c.529T>G

ClinVarID: N/A

CAID: CA350139018

gnomAD: Not found

SupplementalData: More information regarding Lymphocyte subsets and Immunoglobulins in Table I. Table II contains variant information and Table III contains further details about HSCT and a breakdown of each patient's transplant procedure.

Note: No mention of whether or not the patient was tested using transendocytosis.

Case#:1/M. 1.5 y.o. (onset) and 14 y.o. (at assessment), male

DiseaseAssertion: Patient had arthritis, neutropenia and thrombocytopenia, lymphadenopathy, and abdominal pain. The diagnosis of CTLA4 haploinsufficiency was made retrospectively in 7 patients who underwent HSCT for life-threatening, treatment-resistant immune dysregulation and in 1 patient prospectively (unclear which patients were identified retrospectively and prospectively).

FamilyInfo: Father was noted to have Immune dysregulation, Cytopenias and Lymphoma. The patient's father was also noted to have a complex autoimmune disease and died after autologous HSCT for non-Hodgkin lymphoma.

CasePresentingHPOs: HP:0001369 (Arthritis), HP:0001875 (Neutropenia), HP:0001873 (Thrombocytopenia), HP:0002716 (Lymphadenopathy), HP:0002027 (Abdominal pain), HP:0002720 (Decreased circulating IgA level).

CaseHPOFreeText: Autoimmune pancytopenia, Recurrent abdominal pain, Arthritis

This patient was offered HSCT because of ongoing autoimmunity and risk of lymphoma because his father had complex autoimmune disease and died after autologous HSCT for non-Hodgkin lymphoma.

All 8 patients received steroids and a calcineurin inhibitor before transplant

Five patients (including this patient) had peripheral blood HSC grafts and received cyclosporine and mycophenolate mofetil (MMF) for graft versus host disease (GvHD) prophylaxis.

Patient had cytomegalovirus reactivation early post-HSCT and autoimmune hemolytic anemia 6 months post-HSCT, which responded to steroids; he is now off all medication.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient has low levels of IgA but IgG and IgM levels appear to be within normal range. See Table I.

CasePreviousTesting: Not found

GenotypingMethod: Not found

PreviouslyPublished: Yes, Schwab et al. PMID: 29729943

Variant: c.518G>A, p.G173E

ClinVarID: N/A

CAID: CA350138990

gnomAD: Not found

SupplementalData: More information regarding Lymphocyte subsets and Immunoglobulins in Table I. Table II contains variant information and Table III contains further details about HSCT and a breakdown of each patient's transplant procedure.

Note: No mention of whether or not the patient was tested using transendocytosis.

PMID: 34111452

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 29729943

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: Schwab_2018_CaseVV.II.1, male, 7 .o. (onset) 13 y.o. (report), origin in Saudi Arabia, reported Caucasian ethnicity

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Same variant observed in the father. Consanguinity reported

CasePresentingHPOs: HP:0002086, HP:0005523, HP:0011024, HP:0004313, HP:0002720, HP:0001744, HP:0002240, HP:0011947, HP:0002090, HP:0002110, HP:0031035, HP:0002242 (respiratory involvement, lymphoproliferation, gastrointestinal involvement, hypogammaglobulinemia, low IgA, splenomegaly, hepatomegaly, upper and lower RTIs, pneumonia, bronchiectasis, chronic infection, enteropathy, cytopenia (ITP))

CaseHPOFreeText: low IgM, Lymphocytic or granulomatous organ infiltration (lung, liver, gut), GLILD

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: unknown

PreviouslyPublished: no

Variant: c.359_359delG; p.A121fs*23

ClinVarID: not found

CAID: CA2573320362

gnomAD: not found

SupplementalData: extensive phenotype data in figure S1

Case#: Schwab_2018_Patient_129, 16 y.o. (onset) and 19 y.o. (death), male, origin in Germany

DiseaseAssertion: CTLA4 Haploinsufficiency

FamilyInfo: mother (patient 128) was heterozygous with same variant. This patient was recored as 'affected' but type-1 diabetes was the only phenotype reported.

CasePresentingHPOs: HP:0001973, HP:0001945, HP:0001744, HP:0001058, HP:0004313, HP:0004315, HP:0002720, HP:0031378, HP:0002240, HP:0002716, HP:0002093, HP:0000964, HP:0001047 (ITP, fever, splenomegaly, wound healing disorder, hypogammaglobulinemia, low IgG, Low IgA, lymphoproliferation, hepatomegaly, lymphadenopathy, respiratory involvement, eczema, atopic dermatitis)

CaseHPOFreeText: organ infiltration (brain and lung), GLILD, neurological involvement,

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: n/a

CasePreviousTesting: unknown

GenotypingMethod: unknown

PreviouslyPublished: n/a

Variant: NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)

ClinVarID: 161109

CAID: CA173992

gnomAD: not found

SupplementalData: extensive data in S1

Note: functionally tested using transendocytosis

Case#: U.II.1, subject 50. Male. Age of Onset: 3.75 y.o. Age of evaluation: 9 y.o. Origin in Japan, Asian

DiseaseAssertion: Diagnosis with CVID (later with CTLA4 insufficiency)

FamilyInfo: Patient is oldest of three siblings. All three have been genotyped, but only this proband is affected. Variant inherited from the father, who is also unaffected (pedigree in Figure 1).

CasePresentingHPOs: HP:0001873, HP:0001973, HP:0004313, HP:0002720, HP:0004315, HP:0002719, HP:0005353

CaseHPOFreeText: Cytopenia, Autoimmune cytopenia, hypogammaglobulinemia, low IgG, low IgA, Clinically reactivated/apparent Infections, Herpes Infection, clinical EBV infection (possibly chronic?), ITP, positive Coombs test

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Unpublished

Variant: NM_005214.5(CTLA4):c.494G>A (p.W165*)

ClinVarID: N/A

CAID: CA350138939

gnomAD: This variant is not found in gnomAD v2.1.1.

SupplementalData: Extensive data in S1, including some phenotypes that were tested for but found to be absent.

Note: Not functionally tested using transendocytosis.

Case#: T.II.1, subject 48. Male. Age of Onset: 1.5 y.o. Age of evaluation: 21 y.o. Origin in UK, Caucasian.

*DiseaseAssertion: Cytopenia, Evans syndrome

*FamilyInfo: Father had died post autologous HSCT for non-Hodgkin lymphoma. See "supplement 1".

CasePresentingHPOs: ORPHA:1959

CaseHPOFreeText: Severe Psoriatic Arthritis (only patient noted to have it within the study), received a Hematopoietic stem cell transplantation and was one of nine affected mutation carriers still alive and one of three who was more than five years post-HSCT and currently well off all medication at the time of publication.

*CaseNotHPOs: large phenotype table with unreported symptoms in table S1

*CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Slatter, et al. PMID: 27102614

Variant: c.518G>A, p.G173E

ClinVarID: N/A

CAID: CA350138990

gnomAD: Not Found

SupplementalData: extensive data in S1

Note: Not functionally tested using transendocytosis

Case#: Q.II.1, subject 44. Male. Age of Onset: 10 y.o. Age of evaluation/death: 15 y.o. Origin in UK, Caucasian.

DiseaseAssertion: Lymphoproliferation

FamilyInfo: Not found

CasePresentingHPOs: HP:0001744, HP:0002716, HP:0002783, HP:0000964, HP:0001873

CaseHPOFreeText: Three affected mutation carriers (including patient) died following alloHSCT due to GvHD. Patient received transplant due to having Thrombocytopenia and widespread lymphoid hyperplasia despite Rituximab. Patient died four months post transplant due to Acute GvHD Grade IV of the gut. See Table S2.

Lymphocytic or granulomatous organ infiltration - patient's brain was affected. Patient received a biopsy and was found to have B Cell and T Cell infiltration. Vaccination response - Tetanus, Pneumococcal vaccination. Respiratory tract involvement, GLILD, Cytopenia, Splenectomy, Autoimmune cytopenia, ITP, Neurological involvement, Dermatological involvement, Coombs.

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Slatter, et al. PMID: 27102614

Variant: NM_005214.5:c.529T>G

ClinVarID: N/A

CAID: CA350139018

gnomAD: Not found

SupplementalData: extensive data in S1

Note: Not functionally tested using transendocytosis

Case#: OO.II.1, subject 95. Male. Age of Onset: 18 y.o. Age of evaluation: 24 y.o. Origin in Germany, Caucasian.

DiseaseAssertion: CVID

FamilyInfo: Patient was included in group of families who had a documented mutation at Exon: 2 and AA Position: 75. Mutations were: p.R75W (c.223C>T) and p.R75Q (c.224G>A). Family groups were: Family E, Family X, Family JJ, Family UU; Family OO.

CasePresentingHPOs: ORPHA:1572 (CVID), HP:0004313 (Hypogammaglobulinemia), HP:0004315 (Low IgG), HP:0001744 (Splenomegaly), HP:0200117 (Recurrent upper and lower respiratory tract infections), HP:0002090 (Pneumonia), HP:0002110 (Bronchiectasis), HP:0002726 (Recurrent Staphylococcus aureus infections), OMIM:188030 (Immune thrombocytopenic purpura/ITP)

CaseHPOFreeText: Respiratory involvement, Low IgM, Low IgA, Lymphoproliferation, Respiratory tract involvement, GLILD, Cytopenia, Autoimmune cytopenia

Bacterial infection: Hemophilus influenzae

Lymphocytic or granulomatous organ infiltration - Lung.

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.224G>A

ClinVarID: 943305

CAID: CA350138321

gnomAD: Not found

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

Case#: YY.II.1, subject 127. Female. Age of Onset: 3 y.o. Age of evaluation: 14 y.o. Origin in Germany, Caucasian.

DiseaseAssertion: Gastrointestinal involvement

FamilyInfo: None found

CasePresentingHPOs: HP:0001510 (Growth retardation), HP:0001744 (Splenomegaly), HP:0002240 (Hepatomegaly), HP:0002716 (Lymphadenopathy), HP:0200117 (Recurrent upper and lower respiratory tract infections), HP:0002726 (Recurrent Staphylococcus aureus infections), HP:0020114 (Persistent human papillomavirus infection/HPV), HP:0002014 (Diarrhea), HP:0002242 (Enteropathy), HP:0100280 (Crohn's disease), HP:0001047 (Atopic dermatitis), HP:0000964 (Eczema), HP:0200043 (Warts)

CaseHPOFreeText: Lymphoproliferation, Respiratory tract involvement, Dermatological involvement, Liver involvement

Lymphocytic or granulomatous organ infiltration - Liver and gut

Vaccination response - Tetanus, Diphtheria and Pneumococcal

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.326G>A

ClinVarID: 542071

CAID: CA2067088

gnomAD: 2:204735525 G / A

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

Case#: AAA.II.1, subject 130. Male. Age of Onset: 23y.o. Age of evaluation: 46 y.o. Origin in Switzerland, Caucasian.

DiseaseAssertion: Gastrointestinal involvement

FamilyInfo: None found

CasePresentingHPOs: HP:0008207 (Addison's disease), HP:0004313 (Hypogammaglobulinemia), HP:0002720 (Low IgA), HP:0002014 (Diarrhea), HP:0002242 (Enteropathy), HP:0012410 (PRCA/Pure red cell aplasia)

CaseHPOFreeText: Lymphoproliferation, Cytopenia, Autoimmune cytopenia, Endocrinological involvement, Kidney involvement

Lymphocytic or granulomatous organ infiltration of the gut

Thirty-five percent of affected mutation carriers (27/78) were under antibiotic prophylaxis. In one affected mutation carrier (the patient) treatment with vedolizumab (blocking α4β7 integrin) improved colitis, and in the same individual PRCA responded well to cyclosporine A.

IgG levels: no values were available before IVIG or Rituximab

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: Yes, Navarini et al. PMID: 27908448

Variant: NM_005214.5:c.257C>T

ClinVarID: 661941

CAID: CA2067080

gnomAD: 2:204735456 C / T

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

PMID: 33788257

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: Family_A_Patient_A.II.9, male, onset at or before the age of 17, death at age 37 years, ethnicity not specified

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency" or impaired ligand binding by CTLA4 resulting in "a complex syndrome with features of both autoimmunity and immunodeficiency".

FamilyInfo: The Family A pedigree is shown in Figure 1a and includes 39 members and 11 genotype-positive members, of whom 5 are affected.

CasePresentingHPOs: HP:0010444 (Pulmonary insufficiency), HP:0004313 (Decreased circulating antibody level), HP:0001744 (Splenomegaly), HP:0011108 (Recurrent sinusitis), HP:0002837 (Recurrent bronchitis), HP:0000787 (Nephrolithiasis), HP:0032262 (Pulmonary tuberculosis), HP:0032271 (Extrapulmonary tuberculosis), HP:0006532 (Recurrent pneumonia), HP:0025419 (Pulmonary pneumatocele), HP:0030875 (Abnormality of pulmonary circulation), HP:0010976 (B lymphocytopenia), HP:0004313 (Decreased circulating antibody level), HP:0002720 (Decreased circulating IgA level), HP:0002850 (Decreased circulating total IgM)

CaseHPOFreeText: Diagnosis at age 17 was accompanied by hypogammaglobulinemia and splenomegaly. Death at age 37 was due to pulmonary insufficiency. The patient had pulmonary hypertension and clubbing. Lobectomy and lung transplant were performed. Laboratory values included very low B cells and NK cells.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping was performed at the genome-wide level (whole exome sequencing), and additional linkage analysis was performed in this family.

GenotypingMethod: Genotyping was performed by whole exome sequencing as well as genetic linkage analysis with microsatellite markers, linking the disease locus to the D2S1384 marker on chromosome 2 (close to CTLA4).

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: The patient harbors the NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter) variant in the heterozygous state.

ClinVar: 161112

CAID: N/A (Not required, as there is already a ClinVar ID for this variant)

gnomAD: This variant was not found in gnomAD v.2.1.1.

SupplementalData: Yes, the description of the patient is located in the Supplementary Notes, while the clinical phenotypes and laboratory measurements are found in Tables S1 and S2.

PMID: 25329329

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 27221134

Gene: PIK3R1

HGNC: 8979

Disease: Activated PI3K delta syndrome

PMID: 28302518

Gene: PIK3R1

HGNC: 8979

Disease: Activated PI3K delta syndrome

PMID: 35799777

Gene: PIK3CD

HGNC: 8977

Disease: Activated PI3K delta syndrome

Case#: Wang_2022_P13, M, 8 y.o. (diagnosis), origin in

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs:<br /> decreased T cells (HP:0005403) decreased B cells (HP:0010976) decreased CD4/CD8 (HP:0033222) increased IgM (HP:0003496) decreased CD19 increased transitional B cells (HP:0030381) decreased naive b cells (HP:0030372) increased plasmablasts (HP:0032128) decreased CD4 (HP:0032218) decreased CD4 naive (HP:0410378) decresed CD8 naive (HP:0410377) EBV viremia (HP:0020072) lymphadenopathy (HP:0002716) enteropathy (HP:0002242) thrombocytopenia (HP:0001873)

CaseHPOFreeText: increased CD4 CM, increased CD4 EM, increased CD8, increased CD8, CM increased CD8 EM

CaseNotHPOs: abnormal wbc count (HP:0011893) abnormal IgA (HP:0410240) abnormal IgG (HP:0410242) abnormal NK cells (HP:0012176) abnormal memory B cells (HP:0030373)

CaseNotHPOFreeText: abnormal CD3, abnormal CD8 temra, abnormal DNT

CasePreviousTesting:

GenotypingMethod: unclear- possibly WES or NGS

PreviouslyPublished:

Variant: heterozygous NM_005026.5:c.3074A>G (p.E1025G)

ClinVarID: 422410

CAID: CA16617216

gnomAD: Not present in gnomAD

SupplementalData: Table S1

Case#: P7, diagnosed at age 7, female

DiseaseAssertion: APDS

FamilyInfo:

CaseHPOFreeText: recurrent respiratory tract infections, EBV viremia conjunctivitis, lymphadenopathy, hepatosplenomegaly, short stature, thrombocytopenia

GenotypingMethod: Unclear, possibly WES ("In a previous study (15), we reviewed clinical and routine immunological features of 15 APDS patients diagnosed in our center by next-generation sequencing (NGS). In the present study, we extended our previous study...")

Variant: Y524N

CAID: CA338303802

gnomAD: absent from gnomAD v2.1.1

SupplementalData: Table S1

Case#: P23, Male, diagnosed at age 7

DiseaseAssertion: APDS

FamilyInfo:

CaseHPOFreeText: cytomegalovirus, lymphadenopathy, EBV lymphadenitis, B cell lymphoma, IgA vasculitis

GenotypingMethod: Unclear, possibly WES ("In a previous study (15), we reviewed clinical and routine immunological features of 15 APDS patients diagnosed in our center by next-generation sequencing (NGS). In the present study, we extended our previous study...")

Variant: E81K

CAID: CA338300169

gnomAD: absent from gnomAD v2.1.1

SupplementalData: Table S1

PMID: 30499059

Gene: PIK3CD

HGNC: 8977

Disease: Activated PI3K delta syndrome

Case#: Wang_2018_P13, M, 2 y.o. (diagnosis), origin in China

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs: RRTI (HP:0002205) Pneumonia (HP:0002090) Tonsillitis (HP:0011110) Diarrhea (HP:0002014) Lymphadenopathy (HP:0002716) Hepatomegaly (HP:0002240) Splenomegaly (HP:0001744) thrombocytopenia (HP:0001873) mycotic stomatitis (HP:0010280) elevated IgM (HP:0003496)

HP:0002205, HP:0002090, HP:0011110, HP:0002014, HP:0002716, HP:0002240, HP:0001744, HP:0001873, HP:0003496, HP:0010280

CaseHPOFreeText: EBV DNA, CMV-IgM positive, fungus positive, decreased antibodies to Hepatitis-B

CaseNotHPOs: abnormal IgG (HP:0410242), abnormal IgA (HP:0410240)

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: WES + Sanger

PreviouslyPublished:

Variant: heterozygous NM_005026.5:c.3074A>G (p.E1025G)

ClinVarID: 422410

CAID: CA16617216

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S4

Case#: Wang_2018_P3, M, 1 y.o. (onset), origin in China

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs: ----- clincal characteristics at diagnosis (1) Otitis Tonsilitis Pneumonia Mucosanguineous feces Lymphadenopathy (HP:0002716) Hepatomegaly (HP:0002240) Splenomegaly (HP:0001744) Megasplenia Mild anemia Thrombocytopenia Conjunctivitis Left atrial and ventricular enlarged --- Routine immunological (2) decreased b cells decreased CD4/CD8 decreased IgG increased IgM increased IgA ---- clinical manifestations (doc) RRTIs keratitis LAD HSM AIC enteropathy died of infection

CaseHPOFreeText: EBV DNA, fungus negative, CMV-IgM negative

CaseNotHPOs: abnormal wbc counts abnormal IgE abnormal T cells abnormal NK cells autoantibodies

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: WES + Sanger

PreviouslyPublished: Additional info published in 2022 (PMID:35799777)

Variant: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S4

Case#: Wang_2018_P4, M, 8 y.o. (onset), origin in China

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs: ----- clincal characteristics at diagnosis (1) RRTI Pneumonia Diarrhea Lymphadenopathy (HP:0002716) Hepatomegaly (HP:0002240) Splenomegaly (HP:0001744) Rash Inguinal hernia Parotitis Urinary tract infection Perianal abscess --- Routine immunological (2) decreased wbc counts decreased T cells increased NK cells decreased b cells decreased CD4/CD8 decreased IgG increased IgM undetectable IgA ---- lymphocyte subpopulations (2) decreased CD19 increased transitional b cells decreased naive be cells dereased memory b cells increased plasmablasts decreased CD3 decreased CD4 naive decreased CD4 CM increased CD4 EM Increased CD8 decreased CD8 naive decreased CD8 CM ---- clinical manifestations (doc) AIC enteropathy LAD splenectomy short stature

CaseHPOFreeText: EBV DNA, fungus negative, CMV-IgM negative

CaseNotHPOs:<br /> abnormal CD4 autoantibodies

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: WES + Sanger

PreviouslyPublished: Additional info published in 2022 (PMID:35799777)

Variant: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S4

Case#: Wang_2018_P1, M, 2 y.o. (onset), origin in China

DiseaseAssertion: APDS

FamilyInfo: None reported

CasePresentingHPOs: RRTI (HP:0002205) Tonsillitis (HP:0011110) Diarrhea (HP:0002014) Lymphadenopathy (HP:0002716) Hepatomegaly (HP:0002240) Splenomegaly (HP:0001744) ASD (HP:0001631) Dacrocystitis (HP:0000620) Inguinal hernia (HP:0000023) autoimmune cytopenia (HP:0001973) increased transitional B cells (HP:0030381) increased plasmablasts (HP:0032128) decreased CD3 (HP:0045080) increased CD4 (HP:0032219) decreased CD4 naive (HP:0410378) increased CD4 EM (HP:0025625) decreased CD8 naive (HP:0410377) decreased T cells (HP:0005403) decreased b cells (HP:0010976) decreased CD4/CD8 (HP:0033222) decreased IgG (HP:0004315) increased IgM (HP:0003496)

HP:0002205, HP:0011110, HP:0002014, HP:0002716, HP:0002240, HP:0001744, HP:0001631, HP:0000620, HP:0000023, HP:0001973, HP:0030381, HP:0032128, HP:0045080, HP:0032219, HP:0410378, HP:0025625, HP:0410377, HP:0010976, HP:0004315, HP:0003496

CaseHPOFreeText: EBV DNA, decreased antibodies to Hepatitis-B, presence of autoantibodies, decreased CD19, increased CD8, increased CD8 CM, increased NK cells, increased CD8 EM

CaseNotHPOs: abnormal naive B cells (HP:0030370) abnormal memory B cells (HP:0030373) abnormal CD8 TEMRA (HP:0020177) abnormal wbc counts (HP:0011893) abnormal IgA (HP:0410240)

HP:0030370, HP:0020177, HP:0410240, HP:0011893, HP:0020177

CaseNotHPOFreeText: CMV-IgM negative, Fungus negative, abnormal CD4 CM, abnormal DNT

CasePreviousTesting: None reported

GenotypingMethod: WES + Sanger

PreviouslyPublished: Additional info published in 2022 (PMID:35799777)

Variant: NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S4

PMID: 24610295

Gene: PIK3CD

HGNC: 8977

Disease: Activated PI3K delta syndrome

PMID: 29225858

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: N/A. Patient was the only one included in this paper. Male. Age of Onset: 9 y.o. Age of evaluation: 42 y.o onwards. Age of Death: ~49 y.o. Origin in Portugal, ethnicity not specified.

DiseaseAssertion: Evans Syndrome

FamilyInfo: No familial segregation analysis could be performed as the patient′s first‐degree relatives (reportedly healthy) refused genetic testing, and the patient had no progeny. Additionally, when the patient was diagnosed and treated for other health conditions, it was noted that "There was no relevant family history".

CasePresentingHPOs: ORPHA:1959 (Evan's syndrome), HP:0002014 (Diarrhea), HP:4000055 (Intestinal Inflammation), HP:0002719 (Severe/Recurrent Infections), HP:0000403 (Recurrent Otitis), HP:0002254 (Intermittent Diarrhea), HP:0001873 (Severe Thrombocytopenia), HP:0002090 (Pneumonia), HP:0004315 (low IgG), HP:0002720 (low IgA), HP:0001082 (Cholecystitis), HP:0001433 (Hepatosplenomegaly), HP:0008711 (Benign prostatic hypertrophy), HP:0012227 (urethral stricture), HP:0003508 (Proportionate Short Stature), HP:0001888 (Lymphopenia), HP:0410385 (Low levels of CD8+ T cells), HP:0410378 (Low levels of CD4+ T cells),

CaseHPOFreeText: Lymphoproliferation, mild ileal inflammatory infiltrate on histology and hemolysis, lower limb cellulitis, IgE and IgD levels were undetectable, but IgM levels were normal, Bilateral osteonecrosis of femoral head and condyles at age 43, Facial vitiligo, Hemoglobin 12.5 g/L; leukocytes: 8700/μL; platelets 28000/μL, trabeculated bladder.

Duodenal, ileal and bladder biopsy: inflammatory infiltrate (not characterized) Negative: direct Coombs, ANA, EBV DNA, CMV DNA, hepatitis B, C, HIV, proteinuria, urinary Ig loss Antiplatelet Ab positive.

Normal total leukocyte count but patient had lymphopenia.

Antidiphtheria Ab: 0.44 UI/mL (protection titer >1.0 UI/mL); peripheral blood mononuclear cell proliferation to PHA, PPD, and Candida were slightly reduced.

Normal levels of CD3+ and CD4+ but low levels of CD8+ (T cells), Low levels of B cells, NK cells and CD4+ (CD45RA+ and CD45RO+) cells. Normal levels of CD45RA+ but high levels of CD45RO+ (CD8 + T cells).

Born to nonconsanguineous parents.

CaseNotHPOs: N/A

CaseNotHPOFreeText: In 2013, the 45‐year‐old patient was admitted for sepsis. An elective total right hip replacement 6 months before had been followed by recurrent urosepsis. Postoperative diagnosis: recurrent urosepsis caused by Enteroccocus faecalis, Klebsiella pneumoniae and Pseudomonas aeruginosa.

For the next 3 years, the patient remained free of infection on IVIG replacement (0.6–0.8 g/kg) every 3–4 weeks, with a median IgG concentration of approximately 6 g/L. In October 2016, he underwent a transurethral resection of the prostate and soon afterward developed diarrhea and significant weight loss. He was again admitted to our hospital, but after extensive investigation, no infectious or immune‐mediated cause could be found. There was an excellent response to a short course of a higher dose of oral prednisolone (30 mg/day, tapered over the next 2 months to 5 mg/day). In February 2017, he was admitted to his local hospital with left‐sided epididymo‐orchitis and rapidly died from hospital‐acquired pneumonia.

CasePreviousTesting: Broad genetic screening using a custom panel of many immune‐related genes using an ion proton next‐generation sequencer, followed by Sanger sequencing, was performed at the Laboratory of Clinical and Infectious Diseases of the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. See Table 1.

GenotypingMethod: CTLA‐4 sequencing was performed after amplification of the four exons. See Table 1.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.380A>G

ClinVarID: 949358

CAID: CA350138668

gnomAD: Not found

SupplementalData: N/A

Note: Not functionally tested using transendocytosis

PMID: 31396201

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 26478010

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 32562209

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: Yap_2020_P1, male, 52, origin in Italy

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: pedigree in fig 1a. unaffected brother

CasePresentingHPOs: HP:0012378, HP:0046504, HP:0100543, HP:0002028, HP:0030375, HP:0001888, HP:0002242, HP:0001369, HP:0100726 (excessive fatigue, poor libido, cognitive dysfunction, chronic diarrhea, increased memory B cells, lymphopenia, enteropathy, arthritis, Kaposi's sarcoma)

CaseHPOFreeText: diagnosed with cutaneous and nodal cKS secondary to HHV8 infection, hypersomnolence, polyarthralgia, increased DB T cells, decreased SP T cells, decreased CTLA4 expression on Tregs

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: negative for cKS-associated genes: IFNGR1, WAS, STIM1, or TNFRSF4

GenotypingMethod: WGS followed by Sanger sequencing

PreviouslyPublished: not reported

Variant: NM_005214.49(CTLA4):c.457G>A (p.Asp153Asn)

ClinVarID: 636389

CAID: CA350138843

gnomAD: not found

SupplementalData: n/a

note: experimental data (decreased expression in Tregs, figure 1F).

PMID: 31156616

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: Garcia-Perez_2019_B.II.1, male

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: mother is an asymptomatic carrier

CasePresentingHPOs: HP:0100651, HP:0000872, HP:0002242 (Type 1 diabetes, autoimmune thyroidosis, enteropathy)

CaseHPOFreeText: none

CaseNotHPOs: none

CaseNotHPOFreeText: none

CasePreviousTesting: none

GenotypingMethod: Sanger sequencing

PreviouslyPublished: not reported

Variant: NM_005214.5(CTLA4):c.457G>A

ClinVarID: 636389

CAID: CA350138843

gnomAD: not found

SupplementalData: n/a

PMID: 29200144

Gene: CTLA4, PIK3CD

HGNC: 2505,

Disease: CTLA-4 haploinsufficiency, APDS/PASLI

MONDO: MONDO:0014493, MONDO:0018338

InheritancePattern: AD (haploinsufficiency), AD

Prevalence: <1 in 1,000,000. <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete, incomplete

Note: The authors say PI3KCD throughout the article, but I believe they meant PIK3CD.

Case#: Buchbinder_2019_Patient 1, female, 11 y.o. (onset) 21 y.o. (report), Caucasian

DiseaseAssertion: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency

FamilyInfo: "maternal history of vitiligo, hypothyroidism, a maternal grandmother with hypothyroidism, and a maternal great grandmother with multiple sclerosis." mutation was present in the mother, maternal grandmother, and absent in the father.

CasePresentingHPOs: HP:0002113, HP:0001085, HP:0032070, HP:0000988, HP:0002027, HP:0002017, HP:0002014, HP:0001433, HP:0001973, HP:0004313, HP:0001888, HP:0001875, HP:0033608, HP:0002716, HP:0033583, HP:0002729, HP:0001945, HP:0032154, HP:0002829, HP:0032366, HP:0032296, HP:0005479, HP:0100633, HP:0004295, HP:0100279, HP:0032203, HP:0002633, HP:0030374, HP:0045080, HP:0005415, HP:0001882, HP:0002315, HP:0000505, HP:0001250, HP:0000225, HP:0001873

(nodular pulmonary infiltrates, papilledema, leptomeningeal enhancement, recurrent rashes, abdominal pain, vomiting, diarrhea, hepatosplenomegaly, immune cytopenias, hypogammaglobulinemia, lymphopenia, neutropenia, pulmonary nodules, adenopathy, lymphocytic pleocytosis, follicular bronchiolitis, follicular lymphoid hyperplasia, fevers, aphthous ulcerations, arthralgias, presence of direct antiglobulin, elevated IgG level, decreased IgE level, chronic esophagus inflammation, gastric mucosa inflammation, colon inflammation, intramucosal lymphoid nodules in colon, vasculitis, decreased memory B cells, decreased CD3+T, decreased CD8+T, decreased WBC, headache, decreased vision, seizures, gum bleeding, thrombocytopenia)

CaseHPOFreeText: autoantibodies were absent except for a positive direct antiglobulin test. Improvement with corticosteroids, faint oligoclonal bands documented yet absent on subsequent evaluation. brain lesions, elevated CD19+B, decreased NK,

CaseNotHPOs: abnormal bone marrow, abnormal bronchoscopy, abnormal IgA, abnormal IgM, positive anti neuronal antibody test

CaseNotHPOFreeText: n/a

CasePreviousTesting: none

GenotypingMethod: Sanger sequencing of CTLA4

PreviouslyPublished: not reported

Variant: heterozygous for NM_005214.5:c.151C>T

ClinVarID: 161109

CAID: CA173992

gnomAD: not found

SupplementalData: none

Case#: Buchbinder_2019_Patient 2, female, 2 y.o. (onset) 15 y.o. (report), Hispanic

DiseaseAssertion: ADPS/PASLI

FamilyInfo: The mutation was absent in the mother

CasePresentingHPOs: HP:0011947, HP:0031693, HP:0002716, HP:0003496, HP:0001888, HP:0001945, HP:0001433, HP:0001903, HP:0001873, HP:0001744, HP:0033542, HP:0010701, HP:0002720, HP:0003237, HP:0003496, HP:0030374, HP:0030381 (recurrent RTIs, Epstein-Barr virus infection, lymphadenopathy, elevated serum IgM, progressive lymphopenia, fever, hepatosplenomegaly, anemia, thrombocytopenia, splenomegaly, bronchial wall thickening, abnormal quantitative immunoglobulins, decreased IgA, elevated IgG, elevated IgM, decreased memory B cells, elevated transitional B cells)

CaseHPOFreeText: absence of autoantibodies

CaseNotHPOs: HP:0005561 (abnormal bone marrow)

CaseNotHPOFreeText: n/a

CasePreviousTesting: none

GenotypingMethod: Sanger sequencing of PI3KCD

PreviouslyPublished: not reported

Variant: heterozygous for NM_005026.5:c.3061G>A

ClinVarID: 88675

CAID: CA145460

gnomAD: not reported

SupplementalData: n/a

Case#: Grammatikos_2021_Case2, female, 10 months (onset) 25 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Mother and brother are also affected. Extensive family history of autoimmune phenotypes in Figure S1.

CasePresentingHPOs: HP:0002315, HP:000340, HP:0003394, HP:0004313, HP:0012115, HP:0001878, HP:0007565, HP:0001744, HP:0004315, HP:0006577, HP:0002090, HP:0002829, HP:0005263, HP:0006532, HP:0033542, HP:0032174, HP:0002110, HP:0011473 (headache, peripheral paresthesia, muscle cramps, hypogammaglobulinemia, autoimmune hepatitis, hemolytic anaemia, cafe au lait spots, splenomegaly, low IgG, macronodular cirrhosis, fungal pneumonia, arthralgia, antral gastritis, recurrent bacterial pneumonias, bronchial wall thickening, diffuse tree-in-bud infiltrates, bronchiectasis, focal total villous atrophy)

CaseHPOFreeText: Severe lesion in right cerebellar hemisphere and left superior frontal gyrus. Evan's syndrome, bronchial associated lymphoid hyperplasia, intestinal metaplasia, intraepithelial lymphocytes

CaseNotHPOs: HP:0001369, HP:0012538 (artritis, response to gluten)

CaseNotHPOFreeText: n/a

CasePreviousTesting: 2 benign polymorphisms found in perforin gene. Other genes tested: Fas, Fas ligand, Caspase 10, Caspase 8, NRAS. Heterozygous VUS found in LRBA gene.

GenotypingMethod: not specified. It says, "Following her mother’s diagnosis of CTLA4 haploinsufficiency, she was confirmed to have the same genetic mutation." Mother was tested using NGS + Sanger

PreviouslyPublished: not reported

Variant: NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs) heterozygous

ClinVarID: 644629

CAID: CA645516071

gnomAD: not found

SupplementalData: Figure S1 shows extensive family history

Case#: Grammatikos_2021_Case 1, female, 35 y.o. (onset) 51 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: affected younger daughter (case 2), affected son (case 3). 2 brothers of case 1 were affected by Evans syndrome. Another brother was affected by unexplained lymphadenopathy. Deceased brother passed due to eft ventricular fibrosis at age 40. Case 1 also had a niece with recurrent cutaneous ulceration and was a LRBA mutation carrier. The eldest daughter of case 1 developed AML (age 14).

CasePresentingHPOs: HP:0001903, HP:0002716, HP:0001945,HP:0003326, HP:0002829, HP:0031457, HP:0033608, HP:0002110, HP:0001744, HP:0033805, HP:0040312, HP:0002840, HP:0002113, HP:0005479, HP:0010976, HP:0025379, HP:0002922, HP:0001974, HP:0032289, HP:0002321, HP:0002013, HP:0001250, HP:0012534, HP:0001260, HP:0001310 (anaemia, lymphadenopathy, fevers, myalgia, arthralgia, scattered opacification, nodules in lung, bronchiectasis, splenomegaly, non-necrotising granulomas, arthritis of left temporomandibular joint, granulomatous lymphadenitis, migratory infiltrates, decreased IgE, low b-cell count, increased TPO antibodies, increased protein CSF, increased WBC, IgG oligoclonoal pattern, vertigo, vomiting, seizures, right-facial dysesthesia, dysarthria, right-sided dysmetria)

CaseHPOFreeText: mass of 1.4 cm resolving spontaneously behind tibialis posterior tendon. MRI revealed mass in the right middle cerebellar peduncle with surrounding edema. Cellular infiltration by CD4:CD* T cells, plasma cells, microglia (2:1 ratio). Neutrophilic infiltrate of the lymphatic system, EBV-related lymphoprliferation, bile salt malabsorption

CaseNotHPOs: HP:0031693, HP:0005344, HP:0003116 (serum EBV, abnormal carotid ultrasound, abnormal echocardiogram)

CaseNotHPOFreeText: presence of inflammatory markers

CasePreviousTesting: 194 genes associated with immune deficiency, next-gen sequencing. Heterozygous VUS found in LRBA.

GenotypingMethod: confirmation of CTLA4 c.81dup by Sanger sequencing

PreviouslyPublished: not reported

Variant: Heterozygous NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs), Heterozygous NM_006726.4(LRBA):c.6424T>C (p.Phe2142Leu)

ClinVarID: 644629, 1038663

CAID: CA645516071, CA358607456

gnomAD: not found, not found

SupplementalData: Figure S1 shows extensive family history

PMID: 33956248

Gene: CTLA4, LRBA

HGNC: 2505, 1742

Disease: CTLA4 haploinsufficiency

MONDO: MONDO:0014493

InheritancePattern: AD (haploinsufficiency)

Prevalence: <1 in 1,000,000

Penetrance: incomplete

Case#: Grammatikos_2021_ Case3, male, 17 y.o. (onset) 32 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 Haploinsufficiency

FamilyInfo: Mother and sister affected. Extensive family autoimmune history and pedigree recorded in Figure S1.

CasePresentingHPOs: HP:0100651, HP:0000821, HP:0002315, HP:0002018, HP:0002354, HP:0000458, HP:0001973, HP:0001903, HP:0001744, HP:0025379, HP:0025329, HP:0002922, HP:0001882, HP:0032289, HP:0002275, HP:0033693, HP:0008765, HP:0100827 (type 1 diabetes, hypothyroidism, headaches, nausea, memory impairment, anosmia, autoimmune thrombocytopenia, anaemia, splenomegaly, increased TPO antibodies, increased GAD antibodies, increased protein CSF, increased WBC, IgG oligoclonal pattern, poor coordination, olfactory hallucination, auditory hallucination, lymphocytosis)

CaseHPOFreeText: "Electroencephalography confirmed complex partial seizures arising from the right hemisphere and occurring on a background of mild excess of nonspecific slow and theta activity."

CaseNotHPOs: HP:0002693 (abnormal skull base morphology)

CaseNotHPOFreeText: abnormal nasal endoscopy, abnormal upper endoscopy, abnormal venography

CasePreviousTesting: none

GenotypingMethod: not specified. It says, "Following her mother’s diagnosis of CTLA4 haploinsufficiency, she was confirmed to have the same genetic mutation." Mother was tested using NGS + Sanger

PreviouslyPublished: not reported

Variant: NM_005214.4:c.81_82insT (p.Leu28fs)

ClinVarID: 644629

CAID: CA645516071

gnomAD: not found

SupplementalData: Figure S1 shows extensive family history

PMID: 35935971

Gene: CTLA4

HGNC: 2505

Disease: CTLA4 haploinsufficiency

MONDO: MONDO:0014493

InheritancePattern: autosomal dominant

Prevalence: < 1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: Collen_2022_Patient_1, female, infancy (onset) 23 y.o. (report), Ethnicity reported: white

DiseaseAssertion: CTLA4 haploinsifficiency

FamilyInfo: Mutation inherited from father, who had melanoma and was asymptomatic for autoimmunity. Paternal first cousin had type-1 diabetes. Mother and brother had no autoimmune symptoms to report.

CasePresentingHPOs: HP:0002014, HP:0001510, HP:0002608, HP:0003261, HP:0033637, HP:0011473, HP:0002900, HP:0001903, HP:0001944, HP:0002246, HP:0001973, HP:0000872, HP:0008207, HP:0003765, HP:0004315, HP:0410240, HP:0030374 (diarrhea, low growth, celiac disease, elevated TTG IgA, endomyosial antibody, absence of duodenal villi, secondary hypokalemia, anemia, dehydration, scalloping of duodenal folds, cytopenias, hashimoto thyroiditis, Addison disease, psoriasis, low IgG, low IgA, low memory B cells)

CaseHPOFreeText: possible lichen sclerosis, negative titers to varicella-zoster virus and mumps despite vaccination. Patient showed switched memory B cells 1.4%, unswitched memory B cells 4.9%, and intraepithelial lymphocytes. Additional diagnosis's: Celiac disease, Hashimoto thyroiditis, Addison disease, CVID

CaseNotHPOs: HP:0002718 (recurrent bacterial infections)

CaseNotHPOFreeText: abnormal stool culture

CasePreviousTesting: none

GenotypingMethod: Whole exome sequencing (research based)

PreviouslyPublished: not reported

Variant: NM_005214.5:c.457+2T>C

ClinVarID: not found

CAID: CA350138849

gnomAD: not found

SupplementalData: n/a

Note: Functional information present. Immunophenotyping using flow cytometery revealed diminished expression of CTLA4 on CD4+/Foxp3+/CD45RA− memory regulatory T cells (Tregs) (Figure 3A).

Case#: Collen_2022_Patient_2, female, <1 y.o. (onset) 14 y.o. (report), Ethnicity reported: Hispanic

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: reported de novo, but no evidence

CasePresentingHPOs: HP:0002014, HP:0002013, HP:0001508, HP:0001508, HP:0001510, HP:0002018, HP:0002027, HP:0032249, HP:0031035, HP:0005263, HP:0010783, HP:0004313, (diarrhea, vomiting, failure to thrive, lack of growth, chronic nausea, abdominal pain, lung coccidiomycosis, persistent villous atrophy, diffuse stomach inflammation, erythema, mucus plaques, hypogammaglobulinemia)

CaseHPOFreeText: Patient is from an endemic coccidiomyosis region. Increased intra-epithelial lymphocytes, mucoid plaque, scalloping of the duodenum, lamina proprietor expansion, poor response to polysaccharide pneumoccal vaccine

CaseNotHPOs: HP:0002608 (celiac serologies)

CaseNotHPOFreeText: TTG, IgA, EMA, HLA, DQ2, and DQ8 were negative. Bowel wall thickening. abnormal ileocolonoscopy

CasePreviousTesting: Primary immunodeficiency gene panel testing by Invitae

GenotypingMethod: Primary immunodeficiency gene panel testing by Invitae

PreviouslyPublished: not reported

Variant: de novo heterozygous c.71_72del (p.Leu24Profs*35) in exon 1 (NM_005214.5:c.71_72del)

ClinVarID: 1439020

CAID: CA2573320555

gnomAD: not reported

SupplementalData: n/a

MultipleGeneVariants: A heterozygous variant in PLCG2 (c.802C>T, p.Arg268Trp) detected (ClinVarID:403319, CAID:CA8193460). It is not usually reported in the panel. The authors ruled it out because the variant was found in 5 of 66 patients with disseminated coccidiomycosis in PMID:PMC7776098. The variant has been associated with autoimmune diseases according to OMIM. It is present in gnomAD (MAF: 0.101, Ashkenazi Jewish). It has been classified as benign in ClinVar.

PMID:

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency

MONDO: MONDO:0014493

InheritancePattern: autosomal dominant

Prevalence:

Penetrance:

PMID: 32499327

Gene: CTLA4

HGNC: 2505

Disease: CTLA4-related haploinsufficiency

MONDO: MONDO:0014493

InheritancePattern: AD

Prevalence: <1 in 1,000,000

Penetrance: incomplete

Case#: Ayrignac_2020_Patient_3, female, 42 y.o. (onset), origin unknown

DiseaseAssertion: CTLA4-related haploinsufficiency

FamilyInfo: unremarkable family history

CasePresentingHPOs: HP:0001138, HP:0000009, HP:0000572, HP:0020036, HP:0002015, HP:0002167, HP:0001285, HP:0002346, HP:0001272, HP:0002719, HP:0002720, HP:0004315, HP:0002923, HP:0002110 (bilateral axonal optic neuropathy, bladder urgency, vision loss, upper limb dysmetria, speech/swallowing disorder, spastic tetra paresis, head tremor, cerebellar atrophy, recurrent infections, IgA and IgG deficiency, autoantibodies [rheumatoid factor], bronchiectasis)

CaseHPOFreeText: white matter and deep basal ganglia FLAIR hyperintensities

CaseNotHPOs: lymphoproliferation

CaseNotHPOFreeText: abnormal CSF analysis

CasePreviousTesting: CSF analysis, "multiple panel gene excluded the main known causes of inherited leukoencephalopathy, cerebellar ataxia, and mitochondrial diseases."

GenotypingMethod: mini-exome analysis

PreviouslyPublished: n/a

Variant: NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)

ClinVarID: 161109

CAID: CA173992

gnomAD: not reported

SupplementalData: n/a

PMID: 29225858

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 29375547

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 29077208

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 30250467

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

PMID: 8557978

Gene: CTLA4

HGNC: 2505

Disease: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

MONDO: 0014493

InheritancePattern: autosomal dominant

Prevalence: <1 in 1,000,000

Penetrance: The penetrance of the phenotype among carriers of pathogenic variants is incomplete.

Case#: N/A. This patient is the only one studied in this paper. Female. Age of Onset: 11 y.o. Age of evaluation: 13 y.o. Origin not specified but looking at the author information, I believe it can be safely inferred that the patient is originally from Japan.

DiseaseAssertion: Autoimmune enteropathy with CTLA4 haploinsufficiency

FamilyInfo: Patient had no family history of autoimmune diseases, except for hypothyroidism in her mother and hyperthyroidism in her sister. The patient’s mother and sister were found to have the same heterozygous mutation, but they showed only thyroid gland dysfunction that was manageable with medication, which suggests incomplete penetrance.

CasePresentingHPOs: HP:0002720 (low IgA), OMIM:188030 (immune thrombocytopenic purpura (ITP)), sometimes accompanied by HP:0001890 (autoimmune hemolytic anemia), HP:0001882 (leukopenia), and ORPHA:56425 (cold agglutinin disease).

CaseHPOFreeText: Persistent watery diarrhea, immunoglobulin A (IgA) deficiency with low IgG2 and IgG4 subclass, recurrent immune thrombocytopenic purpura (ITP).

The patient had CTLA4 haploinsufficiency and was positive for anti-AIE-75 autoantibody but was successfully treated with 6-mercaptopurine (6-MP)

Patient was suspected of having interstitial nephritis

The patient responded well to prednisolone (PSL; 2 mg/kg/day) that was used to treat ITP at every onset, and the treatment was successfully tapered off. However, watery diarrhea appeared during the tapering of PSL while the treatment for the fifth episode of ITP was ongoing.

Her height was 155 cm (third to fifth percentile) and weight was 48 kg (fifth percentile)

In our patient, clinical remission was achieved with 40 mg/day of PSL. Clinical remission was maintained on 6-MP even after cessation of PSL for 4 years.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: After analyzing the patient’s past laboratory data, we found that following cessation of PSL, ITP relapsed in association with the normalization of IgG levels (861–1,747 mg/dL). In addition, we found that serum levels of sIL-2R were extremely elevated at the onset of AIE. There was no manifestation of AIE, ITP, or other autoimmune diseases for 4 years, while the dose of 6-MP was adjusted to keep the levels of IgG and sIL-2R below 700 mg/dL and 1,500 U/mL, respectively (Fig. 3).

Flow cytometry analysis showed reduced frequency of CD4+ CD25+ FOXP3+ Tregs (Fig. 4) [10]. Consistent with clinical remission of AIE, an endoscopy and histological study 3 years after the achievement of remission demonstrated recovery from villous atrophy (Fig. 5). After 4 years of 6-MP administration, we tried to reduce the amount of 6-MP because we were concerning about the risk of secondary malignancies such as malignant lymphoma caused by 6-MP. Unfortunately, it led to the relapse of diarrhea and ITP along with soar up of serum level of rIL-2 receptor (Fig. 3).

CasePreviousTesting: The patient underwent many different types of testing:

None of the viruses, namely, adenovirus, enterovirus, cytomegalovirus, Epstein-Barr virus, norovirus, and rotavirus, were detected in the patient’s stool sample using polymerase chain reaction. In addition, no pathogenic bacteria were cultured from the stool. Besides, a toxin detection test for Clostridium difficile also yielded negative results. A computed tomography scan of her abdomen revealed a small volume of ascites.

An esophagogastroduodenoscopy and a colonoscopy demonstrated prominent atrophy of the villus in the duodenum (Fig. 1A) and terminal ileum. Colon was intact endoscopically (Fig. 1B). Histopathological examinations of the duodenum and ileum showed severe villous atrophy. Crypt apoptosis, and infiltration of lymphoplasmacytes into the lamina propria were seen in the biopsies of duodenum, ileum, and colon (Fig. 1C-​-E).E). Immunostaining of the normal small intestine tissue with the patient’s serum showed positive staining of the brush borders of the intestinal epithelium, indicating the presence of anti-enterocyte autoantibodies in the serum of the patient (Fig. 2A and ​andB).B). Furthermore, autoantibodies against AIE-75 were detected by Western blotting, using a recombinant protein as an antigen (Fig. 2C). The patient was diagnosed with AIE and was administered an increased dose of PSL (40 mg/day) as induction therapy.

Whole-exome sequencing demonstrated a heterozygous missense mutation in the CTLA4 gene. Flow cytometry analysis showed reduced frequency of CD4+ CD25+ FOXP3+ Tregs

GenotypingMethod: Whole-exome sequencing demonstrated a heterozygous missense mutation in the CTLA4 gene

PreviouslyPublished: Yes, PMID: 29729943. Schwab et al.

Variant: NM_001037631.2:c.119T>C

ClinVarID: None found

CAID: CA350138103

gnomAD: None found

SupplementalData: N/A

Note: Not functionally tested using transendocytosis

Case#: N/A. Patient was the only one included in this paper. Female. Age of Onset: 28 y.o. Age of evaluation: 28 y.o. Origin not specified but looking at the author information, I believe it can be safely inferred that the patient is originally from Japan.

DiseaseAssertion: CTLA4 haploinsufficiency in a patient with Epstein–Barr virus-positive diffuse large B-cell lymphoma and subsequent benign lymphadenopathy

FamilyInfo: A missense mutation in exon 2 of the CTLA4 gene (c.251T>C, p.V84A) was found in the patient’s peripheral blood and buccal cell DNA, but not in her parents’ DNA.

Neither of the parents had this mutant allele of CTLA4 (Figure 3A) and the case was considered to be sporadic.

CasePresentingHPOs: HP:0001047 (Atopic dermatitis), HP:0012378 (fatigue), HP:0001945 (fever), HP:0002716 (Lymphadenopathy/swollen lymph nodes), HP:0001744 (splenomegaly).

CaseHPOFreeText: Mild atopic dermatitis, high fever, multiple swollen lymph nodes, systemic lymphadenopathy and multiple bone lesions.

CTLA4 expression decreased in the peripheral regulatory T cells upon stimulation, whereas CTLA4 and PD-1-positive T cell subsets increased, possibly to compensate for the defective CTLA4 function

Although the patient had no history of autoimmune disease or specific infections, her uncommon clinical course led us to perform genetic screening for congenital immune dysfunction, and a missense germline mutation in CTLA4 was identified.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Immunohistochemistry was performed with antibodies against the following proteins: CD20 (346595, BD Biosciences, San Jose, CA), CD3 (349201, BD Biosciences), CD30 (clone Ber-H2, Roche, Mannheim, Germany), CD15 (Carb-3, Dako, Santa Barbara, CA), Ki-67 (clone MIB-1, Dako), EBV LMP-1 (CS-1-4, Dako), EBV EBNA2 (PE2, Dako), CTLA4 (sc-376016, Santa Cruz Biotechnology, Santa Cruz, CA), and FOXP3 (clone PCH101, eBioscience, San Diego, CA). Immunohistochemistry was performed using an automatic immunostainer (BenchMark, Ventana Medical Systems, Tucson, AZ and BOND-III system, Leica Microsystems, Bannockburn, IL) in accordance with the manufacturer’s instructions.

Epstein–Barr virus detection was performed by in situ hybridization using an EBV-encoded small non-polyadenylated RNA probe on an automated system (Ventana Medical systems for Figure 1B, g, and Leica Microsystems for Figure 2B, e).

Peripheral blood mononuclear cells were separated from the peripheral blood of the patient and two healthy donors using a Ficoll-Paque density gradient (Cedarlane), and total T cells were collected by negative selection using MACS Cell Separation Technology (Miltenyi Biotec, Bergisch Gladbach, Germany). Total RNA was extracted using the RNeasy Mini kit, and complementary DNA (cDNA) was synthesized using a SuperScript III First-Star and Synthesis system (Life Technologies, Carlsbad, CA, USA). qRT-PCR was performed using TB Green Premix Ex Taq II (Takara Bio, Otsu, Japan). The primers used for the amplification are listed in Table 1. The expression levels of FOXP3, CTLA4, and PDCD1 were normalized to that of ACTB.

[18F]-Fluorodeoxy-d-glucose positron emission tomography (FDG-PET)-computed tomography (CT) revealed systemic lymphadenopathy, splenomegaly, and multiple bone lesions (Figure 1A). Laboratory data included increases in lactate dehydrogenase (LDH) to 1,127 IU/L (normal range, 117–236 IU/L), soluble interleukin-2 receptor (sIL-2R) to 10,500 U/mL (145–519 U/mL), and β2-microglobulin to 4.6 µg/mL (1.0–1.9 µg/mL). Serum IgG and IgA moderately decreased to 651 mg/dL (870–1,700 mg/dL) and 28 mg/dL (110–410 mg/dL), respectively, whereas IgM was normal (78 mg/dL; normal range 35–220 mg/dL). The patient’s serum was negative for human immunodeficiency virus-1 antibody.

Histological analysis of the biopsied right axillar lymph node first led to a diagnosis of classic Hodgkin lymphoma (cHL), but the diagnosis was later revised to EBV-positive DLBCL with a T-cell-rich large B-cell lymphoma-like pattern (Figure 1B). The large tumor cells were positive for CD20, CD30 (weak, 30%), and EBV-encoded small RNA (EBER)-in situ hybridization (ISH), and negative for CD3 and CD15. Ki-67 was positive in 80% of the tumor cells. The tumor cells expressed EBV latent membrane protein 1 (LMP-1), but lacked EBV nuclear antigen 2 (EBNA2), and exhibited a type 2 latency pattern (Figure 1C). The patient was treated with one cycle of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), and achieved complete remission.

Two years later, the patient developed cervical lymph node swelling (Figure 2A). Although the relapse of DLBCL was suspected, histological analysis of the biopsied cervical lymph node revealed only reactive follicular hyperplasia with a few, small EBER-positive cells (Figure 2B, a-e). The patient had normal blood cell counts with a relatively low lymphocyte count of 590/µL (normal range, 400–3,700/µL) and normal lymphocyte subsets (CD3+ T cells, 72.1%; CD3+CD4+ T cells, 38.5%; CD3+CD8+ T cells, 28.1%; CD56+ NK cells, 12.7%; CD19+ B cells, 15.2%). However, the serum immunoglobulin levels further decreased (IgG 320 mg/dL, IgA 10 mg/dL, IgM 40 mg/dL). The serum EBV-DNA was 190 copies/µg of DNA when evaluated after 1 cycle of ABVD and became negative after the next cycle of chemotherapy. However, it became positive again half a year before the appearance of lymphadenopathy and remained positive at low levels thereafter (20–60 copies/µg of DNA).

Persisting lymphadenopathy with low immunoglobulin levels and serum EBV-DNA positivity led us to consider the possibility of congenital immune dysfunction.

We evaluated CTLA4 expression upon stimulation of peripheral regulatory T cells, which was markedly reduced according to flow cytometry6 (Figure 3B), and the patient was diagnosed with CTLA4 haploinsufficiency.

GenotypingMethod: The patient’s peripheral blood DNA was screened for germline mutations (Kazusa DNA Research Institute, Chiba, Japan). A missense mutation in exon 2 of the CTLA4 gene (c.251T>C, p.V84A) was found and the mutation was confirmed by Sanger sequencing of the patient’s buccal cell DNA.

PreviouslyPublished: N/A

Variant: NM_001037631.2:c.251T>C

ClinVarID: N/A

CAID: CA350138385

gnomAD: N/A

SupplementalData: N/A

Note: Not functionally tested using transendocytosis

PMID: 36382434

Gene: PIK3CD

HGNC: 8977

Disease: Activated PI3K delta syndrome

PMID: 28167755

Gene: PIK3CD

HGNC: 8977

Disease: Activated PI3K delta syndrome

PMID: 27616589

Gene: PIK3CD

HGNC: 8977

Note: No case-specific evidence. Helpful literature review of the role of PIK3CD and PIK3R1 involvement in APDS.

PMID: 26424649

Gene: PIK3CD

HGNC: 8977

Note: No evidence.

PMID: 27250108

Gene: PIK3CD

HGNC: 8977

Note: No Evidence

PMID: 24136356

Gene: PIK3CD

HGNC: 8977

Case#: Angulo_2014_P5, M, 12 months old (onset), origin in England

DiseaseAssertion: APDS

FamilyInfo: Pedigree in figure 1. Affected sister, son, and niece

CasePresentingHPOs: HP:0002783, HP:0410018, HP:0003496, HP:0005403, HP:0032218, HP:0005415, HP:0010976, HP:0020112, HP:0000365, HP:0002878, HP:0033537, HP:0011950, HP:0001744, HP:0025289, HP:0030387, HP:0030381, HP:0030877 (recurrent lower respiratory tract infection, recurrent ear infection, elevated IgM, decreased T cells, decreased CD4+ T cells, decreased CD8+ T cells, decreased B cells, Increased proportion of CD4+CD25+ regulatory T cells, hearing impairment, type 2 respiratory failure, mosaic attenuation, inflammatory bronchiolitis, splenomegaly, cervical lymphadenopathy, increased class switched memory B cells, increased transitional B cells, mixed obstructive/restrictive FEV1/FVC,

CaseHPOFreeText: increased CD25+ as a percentage of CD3+, increased CD3+CD56+ as % of CD3+, increased proportion of CD4+ CD25+ CD127– CD45RA- regulatory T cells, increased proportion of CD8+ CD25+ CD127– CD45RA+ regulatory T cells, increased CD4+ CD25- CD127– CD45RA- as % of CD4+ peripherally expanded T cells, increased CD8+ CD25- CD127– CD45RA+ as % of CD8+ peripherally expanded t cells, severe necrotising pneumonia, hypoperfused right lung, recurrent salivar gland abscesses, CD

CaseNotHPOs: HP:0410242, HP:0410240 (abnormal IgG, abnormal IgA)

CaseNotHPOFreeText: malignancy

CasePreviousTesting:

GenotypingMethod: WES and Sanger

PreviouslyPublished: not reported

Variant: heterozygous NM_005026.5:c.3061G>A (p.E1021K)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Case#: Angulo_2014_P8, M, 6 months (onset), origin in Slovenia

DiseaseAssertion: APDS

FamilyInfo: de novo confirmed

CasePresentingHPOs: HP:0002783, HP:0410018, HP:0002716, HP:0002014, HP:0032247, HP:0031693, HP:0001433, HP:0000620, HP:0030877, HP:0002720, HP:0003496, HP:0410303, HP:0032218, HP:0010976, HP:0030374, HP:0030388, HP:0030381 (recurrent LRTI, recurrent ear infections, massive generalized lymphadenopathy, cryptosporidium parvum diarrhoea, CMV and EBV infections, hepatosplenomegaly, chronic dacriocystitis requiring surgical intervention, mixed obstructive/restrictive FEV1/FVC, decreased IgA, increased IgM, decreased haemophilus B antibodies, decreased CD4+ T cells, decreased B cells, decreased IgM memory B cells; CD19+ CD27+ IgD+, decreased Class-switched memory B cells; CD19+ CD27+ IgD–, as % of CD19+, increased transitional B cells; CD19+ CD38+ IgM+, as % of CD19+

CaseHPOFreeText: decreased CD25+ as % CD3+, mastocytoma, increased CD8+ T cells, CD4+ CD25– CD127– as % of CD4+ T cells, increased CD8+ CD25– CD127– as % of CD8 T cells, as % of CD19+)

CaseNotHPOs:

CaseNotHPOFreeText: malignancy, abnormal CD4+ CD25+ CD127- as % of CD4+ regulatory T cells

CasePreviousTesting: fibroblast and blood samples taken to evaluate somaticism. Findings indicate the mutation was germline.

GenotypingMethod: WES and Sanger, followed by genome for parental confirmation.

PreviouslyPublished: not reported

Variant: heterozygous NM_005026.5:c.3061G>A (p.E1021K)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Note: could lacrimal gland obstruction be considered atopy for phenotype scoring?

Case#: Angulo_2014_P9, M, 15 months (onset), Irish/Danish ancestry reported

DiseaseAssertion: APDS

FamilyInfo: mother genotype/phenotype positive

CasePresentingHPOs: Recurrent respiratory infection, HP:0002205 Recurrent ear infection, HP:0410018 Splenomegaly, HP:0001744 Increased serum IgM, HP:0003496 Decreased IgG, HP:0004315 Decreased IgA, HP:0002720 Decreased tetanus antibodies, HP:0410295 Low levels of anti-pneumococcal antibodies, HP:0012476 Low levels of anti-Haemophilus Influenzae type B antibodies, HP:0410303 Decreased circulating T cells, HP:0005403 Decreased circulating B cells, HP:0010976 Increased circulating transitional B cells, HP:0030381 Decreased circulating class switched memory B cells, HP:0030388 Bronchiectasis, HP:0002110 lymphadenopathy, HP:0002716

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: WES and Sanger

PreviouslyPublished: not reported

Variant: heterozygous NM_005026.5:c.3061G>A (p.E1021K)

ClinVarID: 88675

CAID: CA145460

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in table S2

Case#: 27-month-old girl Iranian girl

DiseaseAssertion: Combined immunodeficiency.

FamilyInfo: Table2 Mother is a carrier for the variant . CasePresentingHPOs: Annotate with the HPOs presenting specifically in the proband of interest . Case#: 27-month-old girl Iranian girl

DiseaseAssertion: Combined immunodeficiency

FamilyInfo: Table2 Mother ,who has hypothyroidism and a history of frequent respiratory infections in childhood, is a carrier for the variant. Father doesn't carry the variant.

CasePresentingHPOs: HP:0001954 (Recurrent fever) HP:0001369 (Arthritis) HP:0012219 (Erythema nodosum) HP:0031936 (Delayed ability to walk) HP:0000750 (Delayed speech and language development) HP:0001698 (Pericardial effusion) HP:0002205 (Recurrent respiratory infections) HP:0002007 (Frontal bossing) HP:0004315 (Decreased circulating IgG level) HP:0033222 (Decreased CD4:CD8 ratio) HP:0001953 (Diabetic ketoacidosis) HP:0000821 (Hypothyroidism) HP:0100651 (Type I diabetes mellitus)

CaseHPOFreeText: Patient has recurrent hospitalizations. 1) 2mo fever and elevated ESR, CRP 2) 8mo massive pericardial effusion 3) 10mo recurrent pericardial effusion 4) 13 mo high-grade fever and elevated ESR, CRP 5) 18 mo high-grade fever and elevated ESR, CRP 6) 24 mo COVID-19 positive with fever 7) 28 mo COVID-19  gastrointestinal manifestations without any adverse effects.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-exome sequencing was performed on the patient's whole blood sample.

GenotypingMethod: Whole-exome sequencing was performed on the patient’s whole blood sample.

PreviouslyPublished: No

Variant: NM_005026:c.1429G>A p.E477K

ClinVar: Was not found on ClinVar

CAID: CA577192

gnomAD: 0.0003597 https://gnomad.broadinstitute.org/variant/1-9780259-G-A

Case#: Dulau_Florea_2018_10, M, 7 y.o. (report), origin in ?

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs: EBV viremia (HP:0020072), Varicella after live vaccine (HP:0032170), sinopulmonary infection (HP:0005425), lymphadenopathy (HP:0002716), nodular lymph hyperplasia in the intestine (HP:0011956), splenomegaly (HP:0001744),<br /> elevated IgM (HP:0003496), decreased IgG (HP:0004315), decreased IgA (HP:0002720), Granulocytic hyperplasia (HP:0012138),

HP:0020072, HP:0032170, HP:0005425, HP:0002716, HP:0011956, HP:0001744, HP:0003496, HP:0004315, HP:0002720, HP:0012138

CaseHPOFreeText: abnormal IgE, decreased T4/T8 ratio, DAT autoantibodis present, 95% cellularity BM morphology, B cell expansion observed

CaseNotHPOs: lymphoma (HP:0002665)

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: unknown

PreviouslyPublished:

Variant: heterozygous NM_005026.5:c.3061G>A (p.E1025G)

ClinVarID: 422410

CAID: CA16617216

gnomAD: Not present in gnomAD

SupplementalData: Phenotypic info in supplemental table E2

Case#: Ye_2022_PL13, female, 1 yr (onset), Caucasian ancestry reported

DiseaseAssertion: APDS

FamilyInfo:

CasePresentingHPOs: elevated WBCs (HP:0001974) decreased lymphocytes (HP:0001888) decreased NK cell percentage (HP:0040218) lymphoma (HP:0002665)

CaseHPOFreeText: WBCs (15.5 10^9/L) lymphocytes (0.894 10^9/L) NK cell percentage (7%) marginal cell B-cell lymphoma

CaseNotHPOs: abnormal immunoglobulin levels (HP:0010701)

CaseNotHPOFreeText: abnormal B-cell percentage abnormal CD3+ percentage abnormal CD4+ percentage abnormal CD8+ percentage

CasePreviousTesting:

GenotypingMethod: WES from blood sample. WES of tumor also performed to identify somatic variation.

PreviouslyPublished: no

Variant: c.3061G>A, p.E1021K

ClinVarID: 88675

CAID:

gnomAD: NR

SupplementalData: S2 provides more information on the lymphoma.

Case#: Ye_2022_PL16, male, 1.5 yr (onset), Caucasian ancestry reported

DiseaseAssertion: APDS

FamilyInfo: affected, genotype positive half-sibling F2P2 in PMID: 24610295. In this article, identified as PL17. Shared mother most likely has germinal mosaicism.

CasePresentingHPOs: lymphoma (HP:0002665), elevated IgM (HP:0003496) recurrent severe sinopulmonary infections (HP:0005425) otitis media (HP:0000388) lymphadenitis (HP:0002840) rectal abscesses (HP:0005224) cellulitis (HP:0100658) bronchiectasis (HP:0002110) lymphoproliferation (HP:0005523) eczematous dermatitis (HP:0000964) HSV super-infection (HP:0005353) dysmorphic facial features (HP:0001999) osteoporosis complicated by vertebral collapse (HP:0000939) nephrolithiasis (HP:0000787) cholelithiasis (HP:0001081)

CaseHPOFreeText: elevated CD3+ percentage pneumococcal sepsis hypertrophy of lymphoid tissues in the GI tract delayed sexual maturation poor vaccine response

CaseNotHPOs: abnormal IgG (HP:0410242) abnormal IgA (HP:0410240) abnormal lymphocyte count (HP:0040088)

CaseNotHPOFreeText: abnormal B-cell count abnormal CD4+ percentage abnormal CD8+ percentage abnormal NK percentage

CasePreviousTesting:

GenotypingMethod: Targeted sequencing panel of 715 cancer-related genes

PreviouslyPublished: Yes, F2P3 in Crank 2014 (PMID:24610295)

Variant: c.1246T>C, p.C416R

ClinVarID: 132808

CAID:

gnomAD: NR

SupplementalData: S2 provides more information on the lymphoma.

Case#: Ye_2022_PL18, female, 1.5 yr (onset), Caucasian ancestry reported

DiseaseAssertion: APDS

FamilyInfo: family info unreported. Pedigree in Crank 2014 shows potential de novo occurance, but this is not confirmed or commented on.

CasePresentingHPOs: lymphoma (HP:0002665), elevated IgG (HP:0003237), elevated IgM (HP:0003496), decreased B-cell percentage (HP:0010976), recurrent otitis media (HP:0000403), recurrent sinopulmonary infection (HP:0005425), lymphadenopathy (HP:0002716), splenomegaly (HP:0001744), lymphoproliferation (HP:0005523), immune thrombocytopenia (HP:0001973),

CaseHPOFreeText: low CD3+ percentage, decreased CD4+ percentage, elevated NK percentage, decreased vaccine response,

CaseNotHPOs: abnormal IgA (HP:0410240), abnormal lymphocyte count (HP:0040088), abnormal B-cell count (HP:0010975),

CaseNotHPOFreeText: abnormal CD8+ percentage, EBV and CMV

CasePreviousTesting:

GenotypingMethod: Sanger sequencing in original article. These authors perform an additional WES from a blood sample. WES of tumor also performed to identify somatic variation.

PreviouslyPublished: Crank 2014 (PMID:24610295)

Variant: c.3061G>A, p.E1021K

ClinVarID: 88675

CAID:

gnomAD: NR

SupplementalData: S2 provides more information on the lymphoma.

PMID: 33229445

Gene: PIK3CD

HGNC: 8977

Note: NoEvidence. No variant information for PIK3CD, PIK3R1, or PIK3CG.

Case#: P2, 10 year old boy

DiseaseAssertion: APDS

CaseHPOFreeText: presented with recurrent otitis media and sinusitis since his first year of life. He had an adenoidectomy at 3 years of age. He presented with high IgM but normal IgG and IgA serum levels (Table 1). The serum levels of IgG2 (0.23; N: 0.56) and IgG4 (<0.002; N: 0.018) subclasses were low.

CasePreviousTesting: Thus, mutations known to cause APDS1 or APDS2 were searched and excluded by Sanger sequencing

GenotypingMethod: For P2 and P3, a targeted Next-Generation sequencing of a primary immunodeficiencies gene panel including PIK3CD and PIK3R1 was performed

Variant: A heterozygous G to A mutation at position 9775907 (GRCh37; NM_005026.3) in the PIK3CD gene was detected. The mutation leads to an amino acid substitution from glycine to aspartic acid at position 124 (G124D) located in the linker region between the ABD and the RBD at the N-terminal part of p110δ (Figure 1A).

CAID: CA338300460

gnomAD: absent from gnomAD v2.1.1

Case#: P1, 13 year old boy

DiseaseAssertion: APDS

FamilyInfo: no relevant family history was reported.

CaseHPOFreeText: He presented with hypogammaglobulinemia with decreased IgG and IgA but normal IgM serum levels (Table 1). Current complications include bronchiectasis, a lymphoproliferative syndrome with splenomegaly and hepatic fibrosis responsible for portal hypertension associated with gastrointestinal bleedings.

CasePreviousTesting: Thus, mutations known to cause APDS1 or APDS2 were searched and excluded by Sanger sequencing.

GenotypingMethod: Subsequently, to identify the genetic cause of the disease, whole exome sequencing was performed in P1. A heterozygous G to A mutation at position 9775698 (GRCh37; NM_005026.3) on chromosome 1, c.241 G>A in the PIK3CD gene was detected.

Variant: The variation encodes an amino acid substitution from glutamic acid to lysine at position 81 (E81K) located in the ABD at the N-terminal part of p110δ (Figure 1A). Sanger sequencing confirmed the mutation in the patient, which was not present in either parents.

CAID: CA338300169

gnomAD: absent from gnomAD v2.1.1

Case#: P3, 9 year old girl

DiseaseAssertion: APDS

CaseHPOFreeText: presented with growth retardation since 6 months of age (currently −3 SD of height and −2.5 SD of weight). Lymphadenopathy and splenomegaly were noted at the age of 8 years, and adenoidectomy and tonsillectomy were performed. She had decreased IgA but normal IgG and IgM serum levels. Her mother had a similar clinical phenotype and died from Hodgkin lymphoma.

CasePreviousTesting: Thus, mutations known to cause APDS1 or APDS2 were searched and excluded by Sanger sequencing

GenotypingMethod: For P2 and P3, a targeted Next-Generation sequencing of a primary immunodeficiencies gene panel including PIK3CD and PIK3R1 was performed

Variant: A heterozygous G to A mutation at position 9775907 (GRCh37; NM_005026.3) in the PIK3CD gene was detected. The mutation leads to an amino acid substitution from glycine to aspartic acid at position 124 (G124D) located in the linker region between the ABD and the RBD at the N-terminal part of p110δ (Figure 1A).

CAID: CA338300460

gnomAD: absent from gnomAD v2.1.1

PMID: 28428270

Gene: PIK3CD

HGNC: 8977

PMID: 25349153

Gene: PIK3CD

HGNC: 8977

PMID: https://doi.org/10.1002/mgg3.2271

Gene: PIK3R1

HGNC: 8979

Case#: 2-month-old boy

DiseaseAssertion:

FamilyInfo: One healhy brother, noncontributory

CasePresentingHPOs: HP:0025104(Capillary malformation) HP:0004691(2-3 toe syndactyly) HP:0001520(Large for gestational age) HP:0001548(Overgrowth) HP:0033725(Thin corpus callosum) HP:0004315(Decreased circulating IgG level) HP:0002720(Decreased circulating IgA level)

CaseHPOFreeText: At 12 months of age two ear infections occuring four weeks apart and a bilateral eye infection.

CaseNotHPOs: HP:0012759(Neurodevelopmental abnormality) HP:0002850(Decreased circulating total IgM)

CaseNotHPOFreeText: Segmental overgrowth was not observed. Normal newborn bloodspot and hearing screen. Ophthalmology examination is normal. No no evidence for a capillary pial vascular malformation

CasePreviousTesting: Whole-exome sequencing and mtDNA testing

GenotypingMethod: Exome sequencing and mtDNA testing was performed on the patient’s blood sample and cultured fibroblast from a 3 mm punch biopsy from right lower paraspinal region.

PreviouslyPublished: No

Variant: NM_181523.2:c.1746-2A>G p.? 9% of the proband's blood cells (74 sequencing reads) and in 25% of the cultured fibroblasts (84 sequencing reads).

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/1298995/ germline

CAID: CA359883172

gnomAD: Not present in gnomAD

Case#: Case 1, 19 year old male, Romanian

DiseaseAssertion: APDS

FamilyInfo: non-consanguineous parents, Sanger sequencing on the patient and his family members (the father's DNA was unavailable) revealed the E1021K substitution only in the patient, with no history of the disease in the family (Fig. 1A).

CaseHPOFreeText: recurrent respiratory infections, chronic hepatosplenomegaly and nonmalignant lymphadenopathy, acute pericarditis, bronchiolitis, recurrent episodes of upper and lower respiratory tract infections, suppurative otitis media from the 2nd year of life and a severe episode of haemolytic anemia, persistent lymphopenia with decreased naïve CD4 T cells, dysgammaglobulinaemia with an increase of IgM and absence of specific response to anti-pneumococcal vaccination

CasePreviousTesting: WES

GenotypingMethod: WES followed by Sanger

Variant: G > A mutation at the position c.3061 of the PIK3CD gene with E1021K substitution

CAID: CA145460

gnomAD: absent in gnomAD v2.1.1

PMID: 29107464

Gene: PIK3CD

HGNC: 8977

Case#: Case 1, male, Brazilian

DiseaseAssertion: APDS1

FamilyInfo: We identified a kinship that included 3 half-siblings with symptoms typical for APDS1. The patient's father (I.4), a truck driver, reported that in addition to the index case, he had 4 additional children with 3 other women living in different Brazilian cities along his truck route and that 2 of these children (II.4 and II.5) had symptoms similar to the index case (Fig 1A). Of his 5 children, 1 had died at 3 years of age (II.1) with clinical symptoms similar to the index case, including hepatosplenomegaly, fever, and recurrent infections; immunologic studies were not performed. The other symptomatic half-brother (II.5) was evaluated at 5 years of age with a history of 5 episodes of pneumonia, recurrent oral candidiasis, several upper respiratory infections, and hepatosplenomegaly. The pedigree suggested that the father (I.4) carried the same autosomal-dominant PIK3CD mutation that affected 3 sons born to different mothers. However, neither he nor the mothers of the affected boys had any symptoms suggestive of APDS. Sanger sequencing demonstrated that neither the father nor the mothers of the affected boys carried the identified PIK3CD mutation in blood. This raised the possibility of germline or gonadal mosaicism in the father. To test this hypothesis, genomic DNA was extracted from his semen. As illustrated in Figure 1F, semen-derived DNA carried the heterozygous p.E1021K mutation identified in the affected sons. Based on relative peak heights, we estimated that 20% to 25% of the semen carried the mutation.

CaseHPOFreeText: The index case (II.4 in Fig 1A) had 10 episodes of pneumonia, 2 episodes of sepsis, several upper respiratory infections, and oral moniliasis within the first year of life. He subsequently developed hepatosplenomegaly, lymphadenopathy, and an axillary abscess owing to Candida albicans. At 3 years of age, laboratory investigation showed increased immunoglobulin (Ig) M (368 mg/dL) and IgG (1,450 mg/dL) levels, normal IgA level (107 mg/dL), low CD4 (330/mm3) and increased CD8 (1,229/mm3) counts, and low CD19 B cells (17/mm3). IgG subclasses showed normal absolute levels of IgG1 (1,020 mg/dL), IgG2 (79.0 mg/dL), IgG3 (78.3 mg/dL), and IgG4 (28.1 mg/dL); however, their ratio showed a proportional decrease of IgG2.

GenotypingMethod: Sanger sequencing. Unclear if entire PIK3CD gene was sequenced across intron/exon boundaries.

Variant: a heterozygous PIK3CD hotspot mutation (c.3061G→A, p.E1021K) was identified by Sanger sequencing.

CAID: CA145460

gnomAD: absent from gnomAD v2.1.1

PMID: 41346581

Gene: CTLA-4

HGNC: 2505

Case#: 6-year-old female

DiseaseAssertion: Refractory AIHA

FamilyInfo: No family history of related disorders was documented, whole-exome sequencing of the familial trio revealed a novel heterozygous c.362_391del variant in CTLA-4

CasePresentingHPOs: HP:0001903, HP:0000952, HP:0040321, HP:0005505, HP:0001890, HP:0001298, HP:0001973

CaseHPOFreeText: Pale complexion, Hb: 48 g/L, a marked increase in reticulocytes, a positive DAT (IgG 3+, C3d 2+), total bilirubin 44.63 µmol/L, indirect bilirubin 25.32 µmol/L, positive DAT (IgG 3+, C3d 2+), normal glucose-6-phosphate dehydrogenase activity, normal levels of folic acid (6.07 ng/mL) and vitamin B12 (519.95 pg/mL), and bone marrow cytology indicative of hyperplastic anemia, hypertensive encephalopathy

CaseNotHPOFreeText: The ANA profile and antinuclear antibody test were negative, platelet counts remained within the normal range throughout the current disease course

CasePreviousTesting: NR

GenotypingMethod: Whole-exome sequencing

PreviouslyPublished: NR

Variant: NM_005214.5:c.362_391del

CAID: CA3273042436

gnomAD: N/A

SupplementalData: Table 1

PMID: 30639166

Gene: PIK3CD

HGNC: 8977

Case#: Case 1, female, Italian

DiseaseAssertion: APDS1

FamilyInfo: non-consanguineous parents

CaseHPOFreeText: Her clinical history included upper respiratory tract infections during adolescence and an episode of hidradenitis suppurativa at the age of 21 years. Family history was negative for primary immunodeficiencies. Immunological work up showed lymphopenia with hypogammaglobulinemia of all classes and absent response to vaccinations (Supplementary Table 1). T cells were present at normal percentages, while B cells were slightly below the lower range of the norm (Supplementary Table 1). The patient was diagnosed with CVID at 27 years of age and was started on immunoglobulin replacement treatment. During 20 years of follow-up, the clinical course of the patient was particularly mild: she only presented one episode of gastroenteritis at the age of 36 years, and occasional upper respiratory tract infections were treated with oral antibiotics. She has always remained negative for CMV and EBV. Annual abdominal ultrasonography showed a normal spleen size and no lymphoadenopathies. Lung CT scanning did not reveal mediastinal lymphoadenopathies or development of bronchiectasis during sequential lung CT scans (Supplementary Fig. 1). Endoscopic evaluation at 39 years revealed mild gastritis and duodenitis without T cell infiltrate with complete lack of plasma cells (Supplementary Fig. 2). Regarding the immunological evolution during follow-up, lymphopenia was persistent over time (Fig. 1A). In addition, the patient showed a progressive reduction of peripheral B cells (Fig. 1A and Supplementary Table 1) with lack of terminal B cell differentiation (Supplementary Table 2). Bone marrow evaluation showed impaired B cell maturation with an accumulation of precursors at the pro-B to pre-B1 stage (Fig. 1B).

CasePreviousTesting: NGS

GenotypingMethod: NGS followed by Sanger

Variant: c.1973C>T; p.P658L mutation in p110δ

CAID: CA577395

gnomAD: allele frequency of 0.0001114 (2/17954 alleles) in the East Asian population in gnomAD v2.1.1

PMID: 26770665

Gene: PIK3CD

HGNC: 8977

PMID: 21827948

Gene: PIK3CD

HGNC: 8977