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#: 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#: 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#: 2_Edwards_2019, F, 12 yo (report), African American ethnicity reported

DiseaseAssertion: APDS

FamilyInfo: NR

CasePresentingHPOs: EBV + (HP:0430064)

CaseHPOFreeText: NR

CaseNotHPOs: CMV, Lymphoma (HP:0430087, HP:0002665)

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: Yes PMID: 24165795

Variant: PIK3CD c.1002C>A, p.N334K

ClinVarID: 132806

CAID: CA156204

gnomAD: not found

SupplementalData:

Case#: 1_Edwards_2019, F, 40 yo (report), white ethnicity reported

DiseaseAssertion: APDS

FamilyInfo: NR

CasePresentingHPOs: EBV + (HP:0430064)

CaseHPOFreeText: NR

CaseNotHPOs: CMV, Lymphoma

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: Yes PMID: 28414062

Variant: PIK3CD c.371G>A, p.G124D

ClinVarID: 2733822

CAID: CA338300460

gnomAD: not found

SupplementalData:

Case#: 3_Edwards_2019, F, 60 yo (report), white ethnicity reported

DiseaseAssertion: APDS

FamilyInfo: NR

CasePresentingHPOs: EBV +, diffuse large B-cell lymphoma (HP:0430064, HP:0002665)

CaseHPOFreeText: NR

CaseNotHPOs: CMV, Lymphoma (HP:0430087)

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: NR

PreviouslyPublished: No

Variant: PIK3CD c.1573G>A p.E525K

ClinVarID: 132807

CAID: n/a

gnomAD: not found

SupplementalData:

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_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#: 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:

Case#:Patient 7, male, 5 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:The family is French/Chinese

ParentalGenotype:The variant was inherited from Patient 7's asymptomatic mother.

CasePresentingHPOs:HP:0010864, HP:0012758, HP:0000729, HP:0007359, HP:0002069, HP:0032794, HP:0001250, HP:0000252.

CaseHPOFreeText:Patient 7 presents with severe intellectual disability, developmental slowdown, and various seizure types. Patient 7 has Autistic Spectrum Disorder (ASD) and microcephaly.

Patient History

@ 12 months - Patient 7 presented with seizures.

Patient 7 developed additional seizure types including: focal seizures with/without generalization, generalized tonic/clonic/tonic-clonic seizures, myoclonic seizures, and hypomotor seizures.

Patient 7 was on two antiepileptic drugs at most recent followup visit which reduced seizure frequency by >50%.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:The authors selected a cohort of 31 patients with seizure cryptogenic Neonatal/Infantile Epileptic Encephalopathy (NIEE) and seizure onset before 24 months.

Exclusion criteria included: (1) Patients with a definite history of brain insult, malformation of cortical development, neurocutaneous and syndromal disorders, and confirmed or highly suspected neurometabolic disorders based on clinical and biochemical markers. (2) Patients with Dravet syndrome and epilepsy at infancy with migrating focal seizure were also excluded because the majority of variants are detected in the SCN1A (>85%) and KCNT1 (approximately 50%) genes.

Formal neuropsychological testing or best clinical assessment was used to classify patient development or intelligence.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole Exome Sequencing (WES) variant results were filtered in a panel of 430 epilepsy-associated genes. After selection of variants from the 430-gene panel, the synonymous variants, variants with variant frequency <10%, and variants with allele frequency >1% were removed.

Gene:SLC9A6

Variant:Hemizygous splice site NM_001042537.1 c. 794-2A>G was assessed by the authors to be likely pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:CA414750320

gnomAD:Not found

MultipleGeneVariants:Not provided

Case#: case_Kiyota_2018, female,1 yo (onset), Japanese ancestry reported

DiseaseAssertion: APDS + 22q13 deletion syndrome

FamilyInfo: de novo

CasePresentingHPOs: (HP:0001973, HP:0000969, HP:0011134, HP:0000123, HP:0000093, HP:0003073, HP:0004431, HP:0003493, HP:0020151, HP:0033604, HP:0001263, HP:0001290, HP:0000729, HP:0002463, HP:0001249, HP:0007021, HP:0012433

ITP systemic edema mild fever lupus nephritis proteinuria hypoalbuminemia decreased complement levels antinuclear antibody double strand DNA antibody wire-loop lesions in glomeruli delayed psychmotor development hypotonia autistic features language delay intellectual disability reduced sensitivity to pain poor social functioning

CaseHPOFreeText: positive staining for IgG, IgA, IgM, C3 and C1q and electron-dense deposits observed through renal biopsy, along with wire-loop lesions

CaseNotHPOs: (HP:0030882, 0010783, HP:0030880) coronary aneurysm butterfly erythema Raynaud's phenomenon

CaseNotHPOFreeText: dysmorphic features

CasePreviousTesting: G-band karyotyping + whole genome SNP microarray revealed 22q13 deletion syndrome

GenotypingMethod: WES

PreviouslyPublished:

Variant: NM_005026.3:c.1534C > T; p.(Arg512Trp)

ClinVarID: 1347382

CAID: CA577258

gnomAD: v2.1.1 Grpmax 0.00007392 (4/18252 alleles) East Asian population

SupplementalData:

Case#: Hui_2016, female, 2 yo (presentation), origin NR

DiseaseAssertion: APDS

FamilyInfo: variants verified in patient's parents, found to be de novo. It is unclear if case 2 and case 4 are related or unrelated.

CasePresentingHPOs: recurrent respiratory infections, enlargement of lymph node, hepatosplenomegaly, decreased number of native CD4 + T cells, inverted CD4 + /CD8 + T cell ratio and increased IgM, decreased IgA, decreased IgG,

HP:0002205, HP:0002716, HP:0001433, HP:0002720, HP:0032218, HP:0033222, HP:0002720, HP:0003496

CaseHPOFreeText: cytomegalovirus (CMV) or Epstein-Barr virus (EBV) viremia

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: WGS

PreviouslyPublished: NR

Variant: HOMOZYGOUS 3061G>A (E1021K)

ClinVarID: 88675

CAID: N/A

gnomAD: not found in v2.1.1

SupplementalData: unknown

Note: Full access to article denied. Info in annotation gathered from abstract. Also, please be advised the curator translated the article from Chinese to English, and mistranslations are possible.

Case#: 34 year-old Chinese male.

DiseaseAssertion: HAE-C1INH Type 1.

FamilyInfo: Family history of edema (mother passed away due to laryngeal edema, older sister experienced buttock swelling after prolonged sitting, maternal uncle experienced episodic abdominal pain and unilateral upper-limb swelling). Family testing for serum C4 and C1INH concentration and C1INH functional activity indicate that proband’s maternal uncle and asymptomatic daughter exhibit low values for all three of these biochemical markers, consistent with Type 1 HAE. The proband’s daughter and maternal uncle also tested positive for the variant identified in the proband. Pedigree included in figures.

ParentalTesting: Mother passed away before study. Father tested for C4 and C1INH concentration and C1INH function with all values falling in normal ranges.

CasePresentingHPOs: Edema (HP:0000969), Edema of the dorsum of hands (HP:0007514), Edema of the upper limbs (HP:0010742), Non-pitting edema (HP:6000507), Abdominal pain (HP:0002027)

CasePhenotypeFreeText: Onset at approximate age of 26. Episodes of localized edema of limbs, skin, and buttocks lasting two to three days regardless of treatment. Episodes became more frequent at age 34 and were accompanied by abdominal pain triggered by fatigue. Non-pitting edema of right hand observed on physical examination.. The proband’s C4 level was 0.02 g/L (reference range: 0.1–0.4 g/L), C1INH concentration was 0.07 g/L (reference range: 0.21–0.39 g/L), and C1INH functional activity was 4.3% (reference range: ≥68.0%).

CaseNotHPOs: N/A

CaseNotPhenotypeFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification with Sanger sequencing.

Variant: NM_000062:c.1067T>A p.(Val356Glu)

LegacyVariant: N/A

ClinVar: N/A

CAID: CA380702482

gnomAD: N/A

MultipleGeneVariants: N/A

PreviouslyPublished: N/A

AdditionalInfo: N/A

-Gene: DICER1 -PMID: 29343557 -Inheritance Pattern: DICER1 is inherited as an autosomal dominant condition with decreased penetrance -Disease Entity: earlier onset disease, multisite disease, 0-2 site disease, cystic lung disease, familial disease, bilateral disease, stage IA/IB, bilateral disease -mutation: germline loss-of-function mutation, missense mutation, Intronic mutations, hotspot mutation, second somatic mutation, truncating mutations, biallelic mutation -zygosity: heterozygosity -Family History: -testing should be considered for those with a family history of DICER1-associated conditions so that appropriate surveillance can be undertaken. -Individuals at 50% risk of a germline pathogenic variant based on family history who do not pursue genetic testing should follow surveillance guidelines as -if they have a DICER1 mutation unless/until genetic testing confirms that they did not inherit the familial mutation When a pulmonary cyst is identified in a young child with a pathogenic germline -DICER1 variant or family history of a DICER1-associated condition, it should be assumed to be Type I PPB until proven otherwise

Other Information: -Case: Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood -affected phenotype may simply result from probabilities of generating the characteristic “loss-of-function plus hotspot” two hit typical of a DICER1 syndrome neoplasm. -Caseprevioustesting: presymptomatic testing of a minor child, should be discussed and factored into the decision process, as some individuals may choose, and have the right to choose, not to know their/their child’s genetic status. -gnomAD: n/a