Case#: P18, Female, German, 32.2 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Mildly affected based on a CHAI score of 11.11%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.416A>G (p.Tyr139Cys)

ClinVar ID: 623475

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P17, Male, Belgian, 40 years at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.407C>T (p.Pro136Leu)

ClinVar ID: 1711524

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P16, male, german, age: n/a, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 45.83%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.392T>C (p.Val131Ala)

ClinVar ID: 624171

gnomAD: Not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P02, Female, the age of clinical and genetic diagnosis: Unknown, Finnish, alive at the time of article's publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NC_000002.12:g.203868053T>A

ClinVar ID:

CAID: CA350138070

gnomAD: not found in any gnomAD version.

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P15, female, age: n/a, ethnicity: n/a, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.384C>G (p.Ile128Met)

ClinVar ID: 662956

gnomAD: 0.000006814

https://gnomad.broadinstitute.org/variant/2-203870860-C-G?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P01, Female, clinical diagnosis at the age of 45, genetic diagnosis at the age of 56, German, alive at the time of article's publication

DiseaseAssertion: Patient is classified as "Mildly affected" based on a CHAI score of 10.42%.

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.109+1G>T

ClinVar ID: 161113

gnomAD: This variant was not found in any gnomAD version.

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P14, Female, Czech, 36 years old at the time of genetic diagnosis, daed at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: unregistered variant - without the bp change we can't confidently assert this variant at this time but it is possible it is CA2953901753

ClinVar ID: n/a

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

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

Case#: The patient is a 39-year-old female with symptom onset at 14.

DiseaseAssertion: The patient is asserted to have "CTLA-4 happloinsufficiency." "Affected patients develop cytopenia, lymphoproliferative disorders, and hypogammaglobulinemia and are prone to a variety of autoimmune phenomena."

FamilyInfo: None provided

CasePresentingHPOs: HP:0001873 (Thrombocytopenia), HP:0001888 (Lymphopenia), HP:0001903 (Anemia), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0002028 (Chronic diarrhea), HP:0002024 (Malabsorption), HP:0001596 (Alopecia), HP:4000055 (Intestinal inflammation), HP:0006824 (Cranial nerve paralysis), HP:0002090 (Pneumonia), HP:0001269 (Hemiparesis)

CaseHPOFreeText: CSF analysis showed intrathecal synthesis of immunoglobulins G and M. MRI showed disseminated T2-hyperintense lesions, some lesions indicated long-lasting gadolinium enhancement (Figure 1A). PET scan-guided brain biopsy showed sustained myeline integrity, massive infiltration of T cells, and presence of few perivascular B cells. Infectious or neoplastic conditions were ruled out.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Laboratory testing was negative for infectious or rheumatologic conditions. Brain vessel angiography was normal.

CasePreviousTesting: None reported.

GenotypingMethod: Sequencing of the LRBA and CTLA4 genes was performed. Authors did not elaborate on methodology or assay.

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

Variant: The patient is heterozygous for the NM_005214.5(CTLA4):c.322_323insT (p.Ser108MetfsTer46) variant.

CAID: CA3270658428

gnomAD: This variant is not found in gnomAD v4.1.1.

SupplementalData: Figure 1A shows MRI scans from 2014-2021. Figure 1B shows immunomodulatory treatment of the patient. Figure 1C shows blood lymphocyte count and lymphocyte subsets over time. Figure 1D shows Crohn disease activity index, blood platelet count, and serum immunoglobulins. Figure 2 shows single-cell RNA sequencing of peripheral blood monocular cells.

Case#: Patient 2 (P2) is a 23-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's father and oldest sister are both positive for the same CTLA4 variant. Both the parents and two older sisters are asymptomatic. The TNFRSF13B variants were not found in the parents or sisters.

CasePresentingHPOs: HP:0002254 (Intermittent diarrhea), HP:4000055 (Intestinal inflammation), HP:0002582 (Atrophic gastritis), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0030167 (Antimitochondrial antibody positivity)

CaseHPOFreeText: Patient presented at 12 years old with intermittent diarrhea, predominantly mushy stools with ocassional watery stools. Colonoscopy at age 21 demonstrated histopathological evidence of acute and chronic inflammation. Gastroscopy showed chronic atrophic gastritis and duodenitis. Treatment with intravenous immunoglobulin and biweekly subcutaneous abatacept (125 mg) led to clinical improvement.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0032230 (Antineutrophil antibody positivity)

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

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

Variant1: The patient is heterozygous for the NM_005214.4 CTLA4):c.538C>T (p.Leu180Phe) variant.

CAID1: CA350139042

gnomAD1: This variant has a minor allele frequency of 0.0001370 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr2-203871458-C-T?dataset=gnomad_r4).

Variant2: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.83G>A variant.

ClinVar2: 1063279

gnomAD2: This variant has a minor allele frequency of 0.00009130 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16952562-C-T?dataset=gnomad_r4)

Variant3: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.716C>T

ClinVar3: 471370

gnomAD3: This variant has a minor allele frequency of 0.0002962 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16939713-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

Case#: Patient 7 (P7) is a 50-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo:

CasePresentingHPOs: HP:0012735 (Cough), HP:0002014 (Diarrhea), HP:0000988 (Skin rash), HP:0001596 (Alopecia), HP:0004313 (Decreased circulating immunoglobulin concentration), HP:0004386 (Gastrointestinal inflammation)

CaseHPOFreeText: Patient's symptoms onset in his late 30s with respiratory and gastrointestinal symptoms. He developed pruritic rashes on the abdomen and bottom of the feet, as well as alopecia. Gastrointestinal histopathology finding included intestinal metaplasia in the gastric angle and pyloric mucosa, as well as lymphoid follicle formation in the descending duodenum.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity),

CaseNotHPOFreeText: Patient was negative for inflammatory bowel disease antibodies.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

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

Variant1: The patient is heterozygous for the NM_005214.4 CTLA4):c.151C>T(p.Arg51Ter) variant.

ClinVar1: 161109

gnomAD1: The variant was not found in gnomAD v4.1.1.

Variant2: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.788C>T (p.Thr263Ile) variant.

ClinVar2: 1696714

gnomAD2: This variant has an allele frequency of 0.00009138 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16939641-G-A?dataset=gnomad_r4)

Variant3: The patient is heterozygous for the NM_012452.3(TNFRSF13B):c.178C>T (p.Arg60Cys) variant.

CAID3: CA8414096

gnomAD3: This variant has an allele frequency of 0.00006666 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr17-16952467-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

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

Case#: Patient 16 (P16) is a female child, ethnicity not specified.

DiseaseAssertion: The patient is asserted to have CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI)

FamilyInfo: Sanger sequencing of other family members revealed the same CTLA4 variant in seven females across four generations, all of whom are symptomatic with autoimmunity and/or recurrent infections. See Figure 1A for pedigree.

CasePresentingHPOs: HP:0004880 (Respiratory infections in early life), HP:0003256 (Abnormality of te coagulation cascade), HP:0001954 (recurrent fever), HP:0000967 (Petechiae), HP:0002014 (Diarrea), HP:0003270 (Abdominal distention), HP:0025085 (Bloody diarrhea), HP:0001943 (Hypoglycemia), HP:0034315 (Chronic cough), HP:0000010 (Recurrent urinary tract infections), HP:0000076 (Vesicoureteral reflux)

CaseHPOFreeText: In infancy the patient was hospitalized multiple times for respiratory viral infections and an episode of transient coagulopathy. She continued to experience respiratory infections, prolonged bleeding with transient coagulopathy, and intermittent bloody diarrhea. Patient had intermittent elevated lactate. Flow cytometry demonstrated normal lymphocyte subsets and immunoglobulin concentrations were within normal limits. Soluble IL-2 receptor levels were elevated. Gastrostomy tube was placed at 26 months due to recurrent hypoglycemia and poor growth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole exome sequencing performed at 18 months old reported no diagnostic variants. Mitochondrial genome analysis was normal.

GenotypingMethod: Genotyping was performed via whole exome sequencing, which initially did not identify any diagnostic variants. Research analysis of the clinical exome data identified the CTLA4 variant.

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

Variant: The patient is heterozygous for the NM_005214.5: c.654T>A (p.Tyr218*) variant.

ClinVar: 2440604

gnomAD: This variant has an allele frequency of 0.0006536 in gnomAD v4.1.1 (https://gnomad.broadinstitute.org/variant/chr3-38011318-G-A?dataset=gnomad_r4)

SupplementalData: N/A

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.

Case#: Patient 5 (P5) is a 19-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patients mother, who harbors the same CTLA4 variant reported a history of chronic urticaria, alopecia areata, and intermittent diarrhea for over 10 years.

CasePresentingHPOs: HP:0001903 (Anemia), HP:0007418 (Alopecia totalis), HP:0002254 (Intermittent diarrhea), HP:0000964 (Eczematoid dermatitis), HP:0002716 (Lymphadenopathy), HP:0004818 (Paroxysmal nocturnal hemoglobinuria), HP:6000344 (Anti-intrinsic factor antibody positivity), HP:0000988 (Skin rash), HP:0004386 (Gastrointestinal inflammation), HP:0034839 (Lymphoid hyperplasia), HP:0040088 (Abnormal lymphocyte count), HP:0020062 Decreased hemoglobin concentration, HP:0025066 (Decreased mean corpuscular volume), HP:0025547 (Decreased mean corpuscular hemoglobin concentration)

CaseHPOFreeText: Patient's symptoms onset at age 10. Gastrointestinal endoscopy showed chronic inflammation and lymphoid hyperplasia. Patient has been treated with subcutaneous injections of abatacept (125mg) with notable clinical improvement. Fine white hair has started to regrow on her scalp, eyebrows, and eyelashes, and facial skin shows mild scaling.

CaseNotHPOs:

CaseNotHPOFreeText: Autoimmune screening including antinuclear antibodies were negative.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

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

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.151C>T (p.Arg51Ter) variant.

ClinVar: 161109

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: There is no supplemental data.

Case#: Patient 6 (P6) is an 18-year-old Chinese male.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: Patient denied family history of inborn error of immunodeficiency. The patient's father harbors the same CTLA4 variant as the patient. No symptoms are reported in the patient's father.

CasePresentingHPOs: HP:0001954 (Recurrent fever), HP:0012735 (Cough), HP:0002829 (Arthralgia), HP:0002113 (Pulmonary infiltrates), HP:0002716 (Lymphadenopathy), HP:0006532 (Recurrent pneumonia), HP:0004313 (Decreased circulating immunoglobulin concentration

CaseHPOFreeText: MRI of knees showed patchy abnormal signals in the right femoral and lateral condylar regions suggestive of bone marrow edema, with surrounding soft tissue edema. Mild joint effusion and suprapatellar bursa fluid were also noted. Treatment with avatacept was started and at the six-month follow-up the patient reported clinical improvement. He had no fever or sputum production and symptoms of lymphadenopathy and joint pain had improved.

CaseNotHPOs: HP:0001386 (Joint swelling), HP:0000988 (Skin rash), HP:0002014 (Diarrhea), HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity), HP:0002923 (Rheumatoid factor positive), HP:0032230 (Cytoplasmic antineutrophil antibody positivity)

CaseNotHPOFreeText:

CasePreviousTesting: None noted.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

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

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.436G>A(p.Gly146Arg) variant.

ClinVar: 849622

gnomAD: This variant has an allele frequency of 0.000001696 in gnomAD v4.1.1. (https://gnomad.broadinstitute.org/variant/chr2-203870912-G-A?dataset=gnomad_r4)

SupplementalData: There is no supplemental data.

Case#: Patient 1 (P1) is a 24-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's father carries the same CTLA4 variant as the patient but has been asymptomatic. No other family history reported.

CasePresentingHPOs: HP:0031245 (Productive cough), HP:0002105 (Hemoptysis), HP:0001878 (Hemolytic anemia), HP:0006532 (Recurrent pneumonia), HP:0004313 (Decreased circulating immunoglobulin concentration, HP:0033608 (Pulmonary nodule), HP:0002716 (Lymphadenopathy), HP:0001596 (Alpecia),

CaseHPOFreeText: Patient first presented at age 14 with respiratory symptoms. She was hospitalized at age 16 with hemolytic anemia and recurrent pulmonary infections. Lab work showed hypogammaglobinemia. Chest CT showed scattered solid and ground-glass density nodules bilaterally in the lungs, Lung biopsy demonstrated lymphocytic infiltration and siderophages. Treatment with corticosteroids achieved temporary remission, but the patient relapsed with dose tapering. She developed Evans syndrome, alopecia, and skin lesions. Disease stabilized with weekly subcutaneous abatacept (125mg) and the interval was subsequently extended to once every 4 weeks.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0032230 (Cytoplasmic antineutrophil antibody positivity).

GenotypingMethod: Genotyping was performed by whole exome sequencing.

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

Variant: The patient is heterozygous for the NM_005214.4(CTLA4):c.155G>T(p.Gly52Val) variant.

ClinVar: 1420586

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: No supplemental data provided.

Case#: Patient 4 (P4) is a 60-year-old Chinese woman.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: Patient's daughter is Patient 3 and harbors the same CTLA4 variant.

CasePresentingHPOs: HP:0001954 (Recurrent fever) HP:0011110 (Recurent tonsillitis), HP:0000155 (Oral ulcer), HP:0005558 (Chronic leukemia)

CaseHPOFreeText: Patient's symptoms onset in childhood with recurrent fever and tonsillitis. She experienced recurrent oral ulcers starting around age 50. She was diagnosed with large granular lymphocytic (LGL) leukemia for which she was treated with long-term corticosteroids for three years. She is currently treated with oral cyclosporine.

CaseNotHPOs: HP:0000988 (Skin rash)

CaseNotHPOFreeText: Patient denied history of rash, dry mouth, or dry eyes.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

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

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.347T>A (p.Ile116Asn) variant.

ClinVar: 2430678

gnomAD: The variant was not found in gnomAD v4.1.1

SupplementalData: There is no supplemental data.

Case#: Patient 3 (P3) is a 20-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's brother died at age 15 from pancytopenia. The patient's mother was diagnosed with large granular lymphocytic leukemia. Patient's mother (Patient 4) also harbors the same CTLA4 variant as the patient. Authors do not indicate if patient's brother had genetic testing.

CasePresentingHPOs: HP:0001744 (Splenomegaly), HP:0001369 (Arthritis), HP:0020062 (Decreased hemoglobin concentration), HP:0011873 (Abnormal platelet count), HP:0002254 (Intermittent diarrhea), HP:0001876 (Pancytopenia), HP:0020026 (Positive Coombs test)

CaseHPOFreeText: Patients symptoms onset at 9 years old with chronic eczema, Evans syndrome, and splenomegaly. Initially responded well to corticosteroids and IV Ig, but relapsed after steroid tapering. She developed polyarthritis at age 16, diagnosed as juvenile idiopathic arthritis. She also developed photosensitive rashes. She was hospitalized due to pancytopenia and heavy vaginal bleeding. Anti-kertain antibody (AKA) and antiperinuclear factor were negative. Treatment with subcutaneous abatacept injections (125mg) resolved joint pain and brought hemoglobin and platelet counts to normal range.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity), HP:0002923 (Rheumatoid factor positive),

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

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

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.347T>A (p.Ile116Asn) variant.

ClinVar: 2430678

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: There is no supplemental data.

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

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

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#: P05, Male, age: n/a, ethnicity:n/a, alive at the time of publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: <br /> NM_005214.5(CTLA4):c.208C>T (p.Arg70Trp)

ClinVar ID: 161114

gnomAD: 6.195e-7 https://gnomad.broadinstitute.org/variant/2-203870684-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P13, Male, German, 38 years old at the time of clinical diagnosis, 40.6 yeras old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: severly affected based on a CHAI score of 52.38%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENST00000295854.10:c.356T>G

ClinVar ID: not found

CAID:CA350138616

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P12, sex: n/a, age: n/a, ethnicity: n/a

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P11, Female, German, age: n/a, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 18.75%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P10, Female, German, 24 years old at the time of clinical diagnosis, 25 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 33.33%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.326G>A (p.Gly109Glu)

ClinVar ID: 542071

gnomAD: 0.0002354 https://gnomad.broadinstitute.org/variant/2-203870802-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P09, Male, age: n/a, ethnicity: n/a, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.265T>C (p.Tyr89His)

ClinVar ID: 1391402

gnomAD: 0.000003717 https://gnomad.broadinstitute.org/variant/2-203870741-T-C?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P08, Female, Canadian, age: n/a, alive at the time of publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.257C>T (p.Ala86Val)

ClinVar ID: 661941

gnomAD: 0.00001859

https://gnomad.broadinstitute.org/variant/2-203870733-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P07, Male, German, 18 years old at the time of clinical diagnosis and 24.2 years old at the time of genetic diagnosis, alive at the time of publication

DiseaseAssertion: Mildly affected based on a CHAI score of 17.65%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: <br /> NM_005214.5(CTLA4):c.224G>A (p.Arg75Gln)

ClinVar ID: 943305

gnomAD: 0.000008673

https://gnomad.broadinstitute.org/variant/2-203870700-G-A?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P06. Female, German, 52 years old at the time of clinical diagnosis, Alive at the time of publication

DiseaseAssertion: classified as "Severely affected" based on a CHAI score of 47.37%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.214A>C (p.Thr72Pro)

ClinVar ID: 546886

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P04, male, genetic diagnosis at the age of 71.4, ethnicity: N/A, Dead at the time of article's publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.160G>A (p.Ala54Thr)

ClinVar ID: 430905

gnomAD: not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P03, Male, Age: N/A, ethnicity: N/A, Alive at the time of article's publication

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.155G>A (p.Gly52Asp)

ClinVar ID: 871301

gnomAD: not found in any gnomAD version.

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P22, Female, German, age: n/a , alive at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 42.86%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENSP00000497102.1:p.Leu163Ser

ClinVar ID:

CAID: PA2850594025

gnomAD: Not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P21, female, American, age: n/a, alive at the time of publication

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NM_005214.5(CTLA4):c.467C>T (p.Pro156Leu)

ClinVar ID: 1035066

gnomAD: 0.00002292 https://gnomad.broadinstitute.org/variant/2-203871387-C-T?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P20, male, German, 22 years old at the time of clinical diagnosis, 22.7 years old at the time of genetic diagnosis, dead at the time of publication

DiseaseAssertion: Severely affected based on a CHAI score of 42.11%

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: NP_001032720.1:p.Thr147Arg

ClinVar ID:

CAID: PA2850594024

gnomAD: Not found

SupplementalData: Yes, all data regarding the patient was found in Table1.

Case#: P19, Female, Italian, age: n/a, alive at the time of diagnosis

DiseaseAssertion: n/a

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The percentage of transendocytosis using either CD80-GFP or CD80-mScarlet CHO cells was determined in eight LRBA-deficient patients. No difference in the percentage of transendocytosis was observed between CTLA4-variant carriers (GFP median=5.4%; mScarlet median= 49.8%) and LRBA-deficient patients (GFP median=9.9%; mScarlet median, 48.6%). However, significantly lower percentages of transendocytosis were observed in LRBA-deficient patients compared to healthy donors (HD) when using CD80-mScarlet CHO cells (median, 48.6% vs. 65.5% in HD) (Fig. ​(Fig.4e),4e). This difference was not observed with CD80-GFP CHO cells (patients median of 9.9% in patients vs. 13.9% in HD). In conclusion, the CTLA4 transendocytosis method using CD80-mScarlet CHO cells enables the functional verification of LRBA deficiency, but it cannot differentiate between LRBA deficiency and CTLA4 insufficiency.

GenotypingMethod: NGS and Sanger sequencing

PreviouslyPublished: N/A

Variant: ENST00000295854.10:c.434A>G

ClinVar ID:

CAID: CA350138791

gnomAD: 6.197e-7 https://gnomad.broadinstitute.org/variant/2-203870910-A-G?dataset=gnomad_r4

SupplementalData: Yes, all data regarding the patient was found in Table1.

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).

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#: 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#: 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

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.

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#: 20-year-old male, Race: White (ancestry unavailable) DiseaseAssertion: The patient is asserted to have "CTLA4 haploinsufficiency" manifesting as aplastic anemia. FamilyInfo: Patient's father has disease variant Case PresentingHPOs: HP:0012378 (Fatigue), HP:0001962 (Palpitations), HP:0002875 (Exertional dyspnea), HP:0001903 (Anemia), HP:0001873 (Thrombocytopenia), HP:0002608 (Celiac disease), HP:0000608 (Macular degeneration), HP:0001876 (pancytopenia), HP:0001915 (aplastic anemia), CaseHPOFreeText: ** Diagnosis at age 20 when patient presented with persistent and profound incapacitating fatigue. Bone marrow biopsy was consistent to aplastic anemia. Table 1 summarizes presenting labs and flow cytometry results. Patient was first treated with high-dose IVIG, cyclosporine, and systemic corticosteroids. He initially responded well, but 6 months into therapy he developed renal impairment and was transitioned to sirolimus. His aplastic anemia relapsed. Patient underwent haploidentical (sibling, variant negative) hematopoietic stem cell transplantation, which was curative. CaseNotHPOs: HP:4000129 (Recent blood transfusion), CaseNotHPOFreeText: N/A CasePreviousTesting: The following studies were negative: Bone marrow chromosome analysis; FISH hybridization for BCR/ABL1, monosomy 5, monosomy 7, trisomy 8, and 20q deletion; myelodysplastic syndrome mutation sequencing. GenotypingMethod: A primary immunodeficiency NGS panel was run (gene content not specified) and identified a paternally inherited heterozygous missense variant in CTLA4. Variant: The patient is heterozygous for the NM_005214.5(CTLA4):c.385T>A (p.Cys129Ser). ClinVar: 1414930 CAID: N/A gnomAD**: This variant was not found in gnomAD v.4.1.0

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