Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans

Supporting an intramolecular activation mechanism, we found no difference in association of ectopically expressed WT, E81K, or G124D p110δ with endogenous p85α in healthy T cells (see Fig E5, F). [...]the novel E81K and G124D variants of p110δ are hyperactive and can be targeted by p110δ inhibitors. The average error of all time points and conditions for each HDX project was less than 0.2 Da. [...]changes in any peptide at any time point greater than both 7% and 0.7 Da between conditions with a paired t test P value of less than .05 were considered significant. Up and down arrows indicate patient values outside the reference range.F, Female; M, male; ND, not determined. p110δ ABD/linker A.I.1 A.II.1 B.1 Amino acid substitution G124D G124D E81K Age, sex 41, F 11, M(deceased) 13, M EBV EBV lymphadenitis EBV lymphoproliferative disease EBV lymphadenitis Sinopulmonary bacterial infections ✓ ✓ ✓ Lymph node findings ND ND Marginal zone hyperplasia Lymphadenopathy ✓ ✓ ✓ CD4/CD8 ratio 0.53-0.7 ↓(1.11-5.17) 0.2-0.3 ↓(0.7-2.7) 1.41-1.77(0.7-2.4) CD4+ T cells 236-349/μL ↓(359-1565/μL)27.9% to 35.3% ↓(31.9% to 62.2%) 319-564/μL(300-2000/μL)12% to 20% ↓(27% to 53%) 296-403/μL ↓(538-1569/μL)27.7% to 33.8%(23% to 50%) CD8+ T cells 367-655/μL(178-853/μL)48.9% to 52.4% ↑(11.2% to 34.8%) 1726/μL(300-1800/μL)65% ↑(19% to 34%) 172-250/μL ↓(371-436/μL)16% to 21%(15% to 35%) Naive CD4+ T cells (CD45RA+) 16-24/μL ↓(102-1041/μL)∗1.9% to 2.3% ↓(7.6% to 37.7%)∗ ND 82-100/μL ↓(134-969/μL)7% to 8.1%(3% to 33%) Naive CD8+ T cells (CD62L+CD45RA+) 89-110/μL(85-568/μL)8.8% to 11.9%(5.7% to 19.7%) ND ND Effector memory CD8+ T cells (CD62L−CD45RA−) 92-274/μL ↑(24-175/μL)12.3% to 21.9% ↑(1.1% to 9.2%) ND ND Senescent CD8+ T cells (CD57+) 192-320/μL(0-397/μL)21.6% to 25.6% ↑(0% to 16.2%) ND ND CD19+ B cells 17-42/μL ↓(59-329/μL)1.9% to 5.6% ↓(3% to 19%) 27-141/μL ↓(200-1600/μL)1% to 5% ↓(10% to 31%) 387-601/μL(204-703/μL)35% to 46.9% ↑(11% to 25%) Table E1 Extensive clinical table for patients A.I.1, A.II.1, and B.1 Numeric data indicate ranges of patient values listed above age-matched reference ranges in parentheses. A.I.1 A.II.1 B.1 Amino acid substitution G124D G124D E81K Presenting symptoms, age of onset Severe pneumonia, 6 y CVID/ALPS-like, 0.5 y Recurrent skin abscesses and pneumonia, failure to thrive, 0.5 y Viral infections (excluding EBV) Herpes labialis, warts, herpes zoster Varicella after vaccine ND Other bacterial infections MRSA in BAL fluid, Pseudomonas species Otitis media (