Case#: YY.II.1, subject 127. Female. Age of Onset: 3 y.o. Age of evaluation: 14 y.o. Origin in Germany, Caucasian.

DiseaseAssertion: Gastrointestinal involvement

FamilyInfo: None found

CasePresentingHPOs: HP:0001510 (Growth retardation), HP:0001744 (Splenomegaly), HP:0002240 (Hepatomegaly), HP:0002716 (Lymphadenopathy), HP:0200117 (Recurrent upper and lower respiratory tract infections), HP:0002726 (Recurrent Staphylococcus aureus infections), HP:0020114 (Persistent human papillomavirus infection/HPV), HP:0002014 (Diarrhea), HP:0002242 (Enteropathy), HP:0100280 (Crohn's disease), HP:0001047 (Atopic dermatitis), HP:0000964 (Eczema), HP:0200043 (Warts)

CaseHPOFreeText: Lymphoproliferation, Respiratory tract involvement, Dermatological involvement, Liver involvement

Lymphocytic or granulomatous organ infiltration - Liver and gut

Vaccination response - Tetanus, Diphtheria and Pneumococcal

CaseNotHPOs: large phenotype table with unreported symptoms in table S1

CaseNotHPOFreeText: Patient was checked for a number of additional phenotypes but none were identified. Please see Supplementary table S1 for details.

CasePreviousTesting: Genome-wide methods were not used (sequencing of CTLA4 was performed, but no reference made to other genes tested). Some families received whole-exome sequencing but we are unsure if this patient was included.

GenotypingMethod: The authors imply that they sequenced the four exons of CTLA4.

PreviouslyPublished: N/A

Variant: NM_005214.5:c.326G>A

ClinVarID: 542071

CAID: CA2067088

gnomAD: 2:204735525 G / A

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

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#: 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#: 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.