Case#: Case 1, female, Italian

DiseaseAssertion: APDS1

FamilyInfo: non-consanguineous parents

CaseHPOFreeText: Her clinical history included upper respiratory tract infections during adolescence and an episode of hidradenitis suppurativa at the age of 21 years. Family history was negative for primary immunodeficiencies. Immunological work up showed lymphopenia with hypogammaglobulinemia of all classes and absent response to vaccinations (Supplementary Table 1). T cells were present at normal percentages, while B cells were slightly below the lower range of the norm (Supplementary Table 1). The patient was diagnosed with CVID at 27 years of age and was started on immunoglobulin replacement treatment. During 20 years of follow-up, the clinical course of the patient was particularly mild: she only presented one episode of gastroenteritis at the age of 36 years, and occasional upper respiratory tract infections were treated with oral antibiotics. She has always remained negative for CMV and EBV. Annual abdominal ultrasonography showed a normal spleen size and no lymphoadenopathies. Lung CT scanning did not reveal mediastinal lymphoadenopathies or development of bronchiectasis during sequential lung CT scans (Supplementary Fig. 1). Endoscopic evaluation at 39 years revealed mild gastritis and duodenitis without T cell infiltrate with complete lack of plasma cells (Supplementary Fig. 2). Regarding the immunological evolution during follow-up, lymphopenia was persistent over time (Fig. 1A). In addition, the patient showed a progressive reduction of peripheral B cells (Fig. 1A and Supplementary Table 1) with lack of terminal B cell differentiation (Supplementary Table 2). Bone marrow evaluation showed impaired B cell maturation with an accumulation of precursors at the pro-B to pre-B1 stage (Fig. 1B).

CasePreviousTesting: NGS

GenotypingMethod: NGS followed by Sanger

Variant: c.1973C>T; p.P658L mutation in p110δ

CAID: CA577395

gnomAD: allele frequency of 0.0001114 (2/17954 alleles) in the East Asian population in gnomAD v2.1.1