*3.3. Immunogenetics*

HLA class I and II alleles genomic typing were performed and are shown in Supplementary Tables, along with HLA allele frequencies in the Spanish Caucasian population [19]. Case 3 had homozygosity in HLA-DQB1 alleles and Case 1 in HLA-DRB1. Case 1 had the ancestral haplotype 44.3.

The exome analysis performed was negative for Cases 1 and 3. Case 2 showed the heterozygous c.1555A>G (Lys519Glu) variant in the exon 17 of *TCF3* or *E2A* gen, which affects a region not associated with any of the major domains of the transcription factor it encodes. In silico and phylogenetic studies suggested that the affected residue is highly conserved and bioinformatic predictors did not give conclusive results on its pathogenicity. The amino acid substitution slightly modifies the physical–chemical properties of the protein. Databases consulted showed that there are asymptomatic heterozygous carriers in the general population as well as in asymptomatic carriers in families with severe agammaglobulinemia caused by biallelic variants (gnomAD frequency of 0.016%). Case 4 had the heterozygous c.1093G>A (Val365Ile) variant in exon 9 of phosphatase and tensin homolog (*PTEN*) gene, which affected the C-terminal domain of the mature protein phosphatase. In silico and phylogenetic studies suggest that the affected residue is highly conserved among vertebrate species and bioinformatic predictors showed that could be a pathogenic variant (MutationTaster score: 1, DANN score: 0.969). The amino acid substitution slightly modifies the physical–chemical properties of the protein. The database consulted points to a rare variant (gnomAD frequency < 0.01%), only present in two heterozygous carriers from the European population (Supplementary Material S2).
