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#: Female, age of onset: 13, age at testing: 32, age of last documented clinical stability: 34

DiseaseAssertion: suspected hypoactivation of the PI3K pathway

FamilyInfo: maternal grandmother with rheumatoid arthritis, eldest sister died at 4 months due to septic shock after enteritiis

CasePresentingHPOs: HP:0002028, HP:0001945, HP:0025085, HP:0100279, HP:0002090, HP:0012388, HP:0033256, HP:0004313 (recurrent diarrhea, fever, bloody diarrhea, ulcerative colitis (UC), pneumonia, and multiple episodes of acute bronchitis, pancolitis due to Clostridioides difficile infection, hypogammaglobulinemia)

CaseHPOFreeText: salmonellosis, psoriasis and psoriatic arthropathy affecting large joints, reduced B-cell compartment, bronchiectasis suggestive of CVID, unresponsive vaccination test, esophageal dysphagia, neutrophilic esophagitis

CaseNotHPOs: HP:0001249 (intellectual disability)

CaseNotHPOFreeText: dysmorphic features, patient has normal psychomotor and cognitive development,

CasePreviousTesting: clinical exome sequencing

GenotypingMethod: sequencing

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

Variant: NM_005026.5(PIK3CD): [c.2608C > T (p.Arg870)] ; [c.2608C > T (p.Arg870)]

ClinVar: not

CAID:CA338307789

gnomAD: 0.0003%

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

Case#: 10-month‐old Japanese female

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: Her father has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 4. Her paternal grandmother "also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment."

CasePresentingHPOs: HP:0001511, HP:0011220, HP:0000325, HP:0000430, HP:0004322, HP:0000490, HP:0000684, HP:0000331, HP:0000963, HP:0007392

CaseHPOFreeText: Born at 37 weeks of gestation with a birth length of 40.0 cm (−2.9 SD relative to the average for this gestational age) and birth weight of 1,676 g (−3.1 SD relative to the average for this gestational age) (Table 1). Her height and weight were 60.3 cm (−4.0 SD relative to the average for her age) and 4.01 kg (−7.6 SD relative to the average for her age), respectively, at the time of evaluation for the present study. Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 83 mg/dL, 2.6 μIU/mL, and 1.34 ng/mL, respectively, with an HbA1c level of 4.6%. Her HOMA‐IR was 0.53, and her HOMA‐β was 46.8%.

CaseNotHPOs: HP:0000819, HP:0000855, HP:0001382, HP:0000023, HP:0000558, HP:0000400, HP:0000369, HP:0000233, HP:0002714, HP:0005328, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750, HP:0000365

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1c,d

Case#: 20‐year‐old Japanese male

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000819, HP:0000855, HP:0040063, HP:0000484, HP:0000540, HP:0000483, HP:0000646, HP:0000684, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000233, HP:0002714, HP:0100578

CaseHPOFreeText: Born at 39 weeks of gestation with a birth length of 45 cm and a birth weight of 1,990 g (−3.0 SD relative to the average for this gestational age). Weight at time of diagnosis was 38.5 kg (−1.2 SD), height 163.4 cm (−2.7 SD), body mass index 14.4 kg/m2 (−2.1 SD). He was found to have glycosuria during a school urine test at the age of 12 years and started treatment with metformin for diabetes at 15 years. Fasting plasma glucose, serum immunoreactive insulin (IRI) concentrations, and serum C‐peptide at evaluation were 161 mg/dL, 35.8 μIU/mL, and 5.20 ng/mL, respectively. HOMA‐IR was 14.2, and his HOMA‐β was 131.5%. Patient has facial characteristics of SHORT syndrome and adipose tissue atrophy in the upper body.

CaseNotHPOs: HP:0004322, HP:0001382, HP:0000023, HP:0000490, HP:0000558, HP:0000369, HP:0005328, HP:0000545, HP:0000593, HP:0000501, HP:0000963, HP:0007392, HP:0001249, HP:0000750, HP:0000365, HP:0000400

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1

Case#: 6‐year‐old Japanese female

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000855, HP:0004322, HP:0000490, HP:0000684, HP:0000325, HP:0000430, HP:0000400, HP:0000369, HP:0005328, HP:0000545, HP:0000963, HP:0007392, HP:0000365

CaseHPOFreeText: Born with a birth length of 43.1 cm (−1.3 SD relative to the average for this gestational age) and birth weight of 1,544 g (−2.7 SD relative to the average for this gestational age). Her height was 104.0 cm and weight 12.6 kg at the time of evaluation for this study, indicating no apparent short stature (−1.0 SD relative to the average for this age). Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 108 mg/dL, 56.4 μIU/mL, and 6.95 ng/mL, respectively, with an HbA1c level of 5.2%. Her HOMA‐IR was 15.0, and her HOMA‐β was 451.2%. She had a hearing threshold of 30 and 50 dB in the right and left ears, respectively. Otitis media was apparent in the right ear, but not in the left. Patient had readily visible veins.

CaseNotHPOs: HP:0000819, HP:0001382, HP:0000023, HP:0011220, HP:0000331, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750

CaseNotHPOFreeText: N/A

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1, Figure 1a,b

Case#: 33-year‐old Japanese male

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: His daughter has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 3. His mother also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment.

CasePresentingHPOs: HP:0008619, HP:0000365, HP:0000501, HP:0000819, HP:0001511, HP:0004322, HP:0000023, HP:0000490, HP:0000558, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000400, HP:0005328, HP:0100578

CaseHPOFreeText: He was born at 36 weeks of gestation with a birth weight of 1,970 g. Weight at time of diagnosis was 44.2 kg (-2.4 SD), height 154 cm (-3.00SD) , body mass index 18.6 kg/m2 (-1.5 SD). He had been treated with a DPP‐IV (dipeptidyl peptidase‐IV) inhibitor and an SGLT2 inhibitor and manifesting an HbA1c level of 7.4% at the time of the current evaluation. His blood glucose and serum IRI levels at baseline and at 30, 60, 90, and 120 min after the glucose load were 130, 220, 238, 243, and 252 mg/dL and 8.0, 15.5, 25.6, 27.1, and 24.6 μIU/mL, respectively. His HOMA‐IR, HOMA‐β, and insulinogenic index were 2.57, 43.0%, and 0.083, respectively.

CaseNotHPOs: HP:0000855, HP:0001382, HP:0000684, HP:0000369, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000963, HP:0007392, HP:0001249, HP:0000750

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1e,f

Case#: 49-year-old woman

DiseaseAssertion: CTLA-4 deficiency-associated GLILD

FamilyInfo: Family history is negative for hereditary and immunological diseases

CasePresentingHPOs: HP:0031246, HP:0033709, HP:0002094

CaseHPOFreeText: Laboratory tests revealed decreased levels of serum globulin (IgG, IgA, and IgM) and pancytopenia. Serum soluble interleukin-2 receptor levels were elevated within the normal range for angiotensin-converting enzyme levels. Serum antibodies to human immunodeficiency virus (HIV) were within the normal CD4+ T-cell count limit at 1,079 /μL. A flow cytometric analysis demonstrated a decreased number of CD19+CD27+ memory B cells in the blood, with a selective decrease in IgG- and IgA-producing memory B cells. Chest radiography revealed bilateral infiltration of the lower lung fields while chest CT showed bilateral lower lobe reticular shadows as well as right middle lobe infiltrative and scattered nodular shadows in both the upper lobes. Bronchoalveolar lavage (BAL) showed increased cell counts (5.5×104/μL) and increased eosinophils, neutrophils, and lymphocytes in the cell fraction (eosinophils, 7%; neutrophils, 3%; lymphocytes, 25%; macrophages, 65%). The CD4/CD8 ratio in the lymphocytes was within the normal range (CD4/CD8 ratio: 1.06). A transbronchial lung biopsy revealed mild lymphocytic and eosinophilic infiltration of the cell septa. A pathological examination at low magnification revealed collapsed alveolar spaces with surrounding fibrotic changes, and at high magnification, thickened alveolar walls, nodule formation with lymphocyte and plasma cell infiltration, and lymphatic follicles were found. Polypoid plugs of loose organizing connective tissue (Masson bodies) within alveoli and small granulomas were also present. The infiltrated lymphocytes were CD3- or CD20-positive.

CaseNotHPOFreeText: Autoantibodies also tested negative. Bacterial and mycobacterial culture for chronic lower respiratory tract infections were negative. IgG4-positive cells were not detected. There was no neutrophil accumulation or presence of fungus, Gram-positive and/or Gram-negative bacteria, or acid-fast bacteria that would have suggested infection. No findings of vasculitis or malignant tumors were noted.

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: NR

Variant: NM_005214.5:c.160G>A

ClinVar: 430905

CAID: CA350138187

gnomAD: NR

SupplementalData: Table, Fig 1a-c, Fig 2a-f

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#: 7-year-old boy

DiseaseAssertion: Atrial flutter (AFL), sick sinus syndrome (SSS), Brugada syndrome (BrS)

FamilyInfo: Family history of sudden death in maternal grandfather at age 30 years. Family testing identified the same SCN5A variant in the proband's mother and sister. The mother was asymptomatic but had a coved type ST elevation in V1 lead recorded at the 3rd intercostal position (Fig. 1e) and remained free of cardiac events until age 37 years. His sister's ECG was normal, and she remained free of cardiac events for 10 months

ParentalTesting: Mother was found to have the same LOF variant

CasePresentingHPOs: HP:0004749, HP:0011712, HP:0011704, HP:0011654

CaseHPOFreeText: AFL detected on ECG with right bundle branch block but no history of arrhythmia, congenital heart disease, or cardiomyopathy. Post-RFCA, patient had sinus arrest lasting up to 7s, leading to diagnosis of sick sinus syndrome (SSS). Post-ablation ECG following a second RFCA revealed Brugada-type patterns, raising suspicion of Brugada syndrome (BrS) which eventually lead to a diagnosis.

CaseNotHPOs: HP:0001638, HP:0001279, HP:0011675

CaseNotHPOFreeText: Cardiomyopathy, syncope, arrhythmia

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: c.2678G > A p.Arg893His

ClinVar: 67749

CAID: CA016396

gnomAD: https://gnomad.broadinstitute.org/variant/3-38585800-C-T?dataset=gnomad_r4 (v4.1.0 GrpMax FAF: 0.000003390 (European non-Finnish) )

Case#: 55-year-old man

DiseaseAssertion: single coronary artery (SCA) and presented with dilated cardiomyopathy (DCM)

FamilyInfo: Unremarkable

ParentalTesting: NR

CasePresentingHPOs: HP:0002094, HP:0031352, HP:0001638, HP:0001644, HP:0010741

CaseHPOFreeText: chest tightness and dyspnoea after activity lasting for 2 months. CTCA showed congenital absence of the right coronary artery. TTE revealed enlargement of the left heart and cardiomyopathy. CMR revealed DCM. oedema of both lower limbs. Laboratory data in Table 1.

CaseNotHPOs: NR

CaseNotHPOFreeText: Stenosis

CasePreviousTesting: See NGS results in Supplementary Table 1

Genotyping Method: Genetic screening (NGS results in Supplementary Table 1) with confirmation by Sanger

FunctionalAnalysis: NR

Variant: c.1858C>T (p.Arg620Cys)

ClinVar: 67694

CAID: CA015449

gnomAD: v4.1.0 GrpMax FAF: 0.00002033 (European non-Finnish)

AdditionalInfo: The patient also has APOA5:c.990_993delAACA (p. Asp332Valfs*5) (P/LP in ClinVar with 2 stars)