Case#: OO.II.1, subject 95. Male. Age of Onset: 18 y.o. Age of evaluation: 24 y.o. Origin in Germany, Caucasian.

DiseaseAssertion: CVID

FamilyInfo: Patient was included in group of families who had a documented mutation at Exon: 2 and AA Position: 75. Mutations were: p.R75W (c.223C>T) and p.R75Q (c.224G>A). Family groups were: Family E, Family X, Family JJ, Family UU; Family OO.

CasePresentingHPOs: ORPHA:1572 (CVID), HP:0004313 (Hypogammaglobulinemia), HP:0004315 (Low IgG), HP:0001744 (Splenomegaly), HP:0200117 (Recurrent upper and lower respiratory tract infections), HP:0002090 (Pneumonia), HP:0002110 (Bronchiectasis), HP:0002726 (Recurrent Staphylococcus aureus infections), OMIM:188030 (Immune thrombocytopenic purpura/ITP)

CaseHPOFreeText: Respiratory involvement, Low IgM, Low IgA, Lymphoproliferation, Respiratory tract involvement, GLILD, Cytopenia, Autoimmune cytopenia

Bacterial infection: Hemophilus influenzae

Lymphocytic or granulomatous organ infiltration - Lung.

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.224G>A

ClinVarID: 943305

CAID: CA350138321

gnomAD: Not found

SupplementalData: extensive data in S1

Note: Functionally tested using transendocytosis

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.