Case#: Female, age of onset: 56, age at testing: 69, age of last documented clinical stability: 74

DiseaseAssertion: suspected hyperactivation of the PI3K pathway; implied earlier in the paper as "activated PI3Kδ syndrome (APDS)"

FamilyInfo: no relevant family history

CasePresentingHPOs: HP:0001878, HP:0012735, HP:0000975, HP:0002716, HP:0012387, HP:0001744, HP:6000143, HP:0004313, HP:0002721, HP:0006530, HP:0002788 (hemolytic anemia, cough, diaphoresis, lymphadenopathy, bronchitis, splenomegaly, perforated appendicitis, hypogammaglobulinemia, immunodeficiency, interstitial lung disease, recurrent upper respiratory tract infections)

CaseHPOFreeText: asthenia, sarcoidosis due to chronic granulomatous sarcoid-type inflammation without necrosis, bronchiectasis with bronchiolitis, wound infection, abdominal wall dehiscence, common variable immunodeficiency (CVID) with immune dysregulation, CVID-associated interstitial lung disease, granulomatous-lymphocytic interstitial lung disease

CaseNotHPOs: HP:0012759 (neurodevelopmental abnormalities)

CaseNotHPOFreeText: dysmorphic features, learning difficulties

CasePreviousTesting: clinical exome sequencing targeting genes associated with primary immunodeficiencies

GenotypingMethod: sequencing

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

Variant: NM_181504.3(PIK3R1):c.5A > T (p.Tyr2Phe)

ClinVar: not found

CAID:CA3290217

gnomAD: 0.3004% https://gnomad.broadinstitute.org/variant/5-67586561-A-T?dataset=gnomad_r2_1

SupplementalData: There is no supplemental data, clinical timeline and schematic with noted variants are in Figure 2 and Figure 3

Case#: P1

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText:

CasePreviousTesting: WES

Variant: E1021K

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

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P2

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (1 m), pulmonary artery hypertension, bronchiectasis (16 y), Lymphadenomegaly, splenomegaly, hepatomegaly, Thrombocytopenia, Pericardial effusion, kidney injury, hypoalbuminemia, failure to thrive, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

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

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P3

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Pneumonia, Recurrent respiratory tract infections (6 m), bronchiectasis (7 y), Lymphadenomegaly, splenomegaly, hepatomegaly, Pericardial effusion, warts, proteinuria, hypoalbuminemia, intracranial hypertension, convulsion, failure to thrive, nasosinusitis, mastoiditis, brain atrophy, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1021K

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

ClinVar: 88675

CAID: CA145460

gnomAD: https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Case#: P10

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Purpura, Recurrent respiratory tract infections, bronchiectasis (9 y), Chronic diarrhea, colitis, ileitis, gastritis, Lymphadenomegaly, splenomegaly, hepatomegaly, ITP, Mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E1025G

HGVS: NM_005026.5(PIK3CD):c.3074A>G (p.Glu1025Gly)

ClinVar: 422410

CAID: CA16617216

gnomAD: absent from gnomad v4.1.0

Case#: P17

DiseaseAssertion: APDS1

FamilyInfo: Chinese

CaseHPOFreeText: Upper respiratory infection, Recurrent respiratory tract infections (1.5 y), bronchiectasis (7 y), otitis media, hearing loss, Lymphadenomegaly, splenomegaly, hepatomegaly, ILD, Kidney stones, oblique inguinal hernia, failure to thrive, mastoiditis, anti-infection prophylaxis, IVIG, glucocorticoid, mTOR inhibitor.

CasePreviousTesting: WES

Variant: E525G

HGVS: NM_005026.5(PIK3CD):c.1574A>G (p.Glu525Gly)

ClinVar: 582515

CAID: CA338303813

gnomAD: absent from gnomad v4.1.0

Case#: 15-year-old Chinese boy

DiseaseAssertion: Patient was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD. Diagnoses: Activated PI3Kδ syndrome

FamilyInfo: Family history revealed that his mother died of gastric cancer. Whole exome sequencing was performed in patient and in his father, when he was at the age of 15 and the PIK3CD gene was found to exhibit good coverage.

CasePresentingHPOs: HP:0002725, HP:0005425, HP:0032218, HP:0002716, HP:0000093, HP:0020072, HP:0000790, HP:0001882, HP:0001903, HP:0003493, HP:0025289, HP:0001744, HP:0004322, HP:0550004, HP:0001873, HP:0003565, HP:0011227, HP:0020026, HP:0032230, HP:0002110, HP:6001383, HP:0033726, HP:0033493, HP:0012574

CaseHPOFreeText: Serum level of complements was low, such as C3, C4, and CH50. Serum level of IgM and IgE was elevated, but IgG and IgA was normal. Lung CT scan showed partial consolidation of left upper lung with bronchiectasis and left upper bronchial stenosis. Renal biopsy was also done because of persistent hematuria and proteinuria, and it displayed moderately increased mesangial matrix and mesangial hypercellularity under the light microscope; subepithelial deposits was noted, and some mesangial changes may be present as seen in electron microscopy. Immunofluorescence was positive for C1q, C3, IgG, IgM, and Fb (Fig. 2). The patient was given oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil. Six months later, the level of complement was restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. He was currently receiving intravenous immunoglobulin in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil, with a good efficacy.

CasePreviousTesting: NR

GenotypingMethod: Whole exome sequencing, Sanger sequencing

PreviouslyPublished: No

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

ClinVar: 88675

gnomAD: chr1-9726972-G-A

SupplementalData: Figure 1, 2, 3

Case#: 3-year-old male

DiseaseAssertion: Activated phosphoinositide 3-kinase delta syndrome (APDS)

CasePresentingHPOs: HP:0034839, HP:0005425, HP:0020071, HP:0012189

CaseHPOFreeText: We describe a 3-year-old patient with a novel variant in the PIK3CD gene (c.58G > A p.(Val20lle)) presenting with EBV viremia, Hodgkin lymphoma, upregulation T follicular helper cells and CD10 + B cells consistent with a phenotype of APDS in a 3-year-old boy.

Variant: c.58G > A p.(Val20lle)

CAID: 1359338