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_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.

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

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

Case#: Takeda_2017_B.1, male, 0 years (onset)

DiseaseAssertion: APDS

FamilyInfo: unaffected mother was tested and found not to have the variant. Father was unavailable for testing

CasePresentingHPOs: abscess, severe diaper rash, recurrent otitis media, eczema, pneumonia, bloody stool, lymphoma, poor growth, low bone age, hypergammaglobulinema lymphocytopenia, elevated transitional B cells, sinopulmonary bacterial infection, decreased CD4+ T cell, decreased CD8+ T cells, decreased naive CD4+ T cells

(HP:0025615, HP:0011131, HP:0000403, HP:0000964, HP:0002090, HP:0025085, HP:0002665, HP:0002716, HP:0001510, HP:0002750, HP:0010702, HP:0001888, HP:0030381, HP:0005425, HP:0032218, HP:0005415, HP:0410378)

CaseHPOFreeText: marginal zone hyperplasia, EBV lymphadenitis, increased CD19+ B cells

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: NR

GenotypingMethod: WES + Sanger

PreviouslyPublished: NR

Variant: c.241G>A (p.E81K)

ClinVarID: NR

CAID: CA338300169

gnomAD: NR

SupplementalData:

Xu, G., Qi, F., Li, H., Yang, Q., Wang, H., Wang, X., Liu, X., Zhao, J., Liao, X., Liu, Y., Amit, I., Liu, L., Zhang, S., & Zhang, Z. (2020). The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. MedRxiv, 2020.08.15.20175638. https://doi.org/10.1101/2020.08.15.20175638