Submission Details

OMIM entities: Roifman-Chitayat syndrome, digenic (613328), Immunodeficiency 14A, autosomal dominant (615513), Immunodeficiency 14B, autosomal recessive (619281).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, multiple disease assertions are made in the literature with differences in inheritance and molecular mechanism(s) although phenotypic variability is less stark among the above mentioned disease entities. Therefore, the AD and AR phenotypes have been split in to separate curations. Roifman-Chitayat syndrome (613328) is split as well, but not curated due to digenic inheritance.

The relationship between PIK3CD and immunodeficiency 14, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2022. PIK3CD encodes Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (P110δ), which binds to the p85 regulatory subunit and effects mTOR/AKT phosphorylation. Immunodeficiency 14, also known as Activated PI3K Delta Syndrome 1 (APDS1), is characterized by recurrent infections (often sinopulmonary), hypogammaglobulinemia, splenomegaly, lymphoid nodules on mucosal surfaces, abscesses, decreased circulating B cells, autoimmunity (cytopenias), B-lymphoma (PMIDs: 29599784, 24165795, 24610295, 30738173).

PIK3CD was first reported in relation to autosomal dominant immunodeficiency 14 in 2006 by Jou et al (PMID: 16984281); however, detailed description of the gene variant or the phenotype was not provided. Angulo et al, 2013 (PMID: 24136356) and Lucas et al, 2014 (PMID: 24165795) studied a large number of individuals with APDS and reported variants in PIK3CD. A few pathogenic missense variants have been reported in humans in the ClinVar database. The E1021K variant is the most frequently observed variant in affected individuals, accounting for about 85% of disease (PMID: 31111319). The PIK3CD gene is highly constrained for missense variation (Z= 4.27, gnomAD v2.1.1). Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 22 probands in 12 publications (PMID: 27697496, 30499059, 2810446, 24165795, 33080915, 31031754, 27426521, 30138677, 28578023, 28414062, 24136356, 16984281). Multiple reports of the E1021K are available in the literature but a founder effect is ruled out and the variants are thought to have arisen independently (PMID: 24136356). Some of the variants, including the E1021K variant, are also proven de novo variants. The mechanism for disease is gain of function and missense variants found across the gene can cause activation of PI3Kδ.

Summary of experimental data (6 points): This gene-disease association is supported by in vitro functional assays and animal models. PIK3CD interacts with PIK3R1 and performs a similar function (PMID: 9235916, 28167755). It is predominantly expressed in leukocytes (PMID: 9235916). Several knock-in mouse models have been reported in the literature that recapitulate the cellular phenotype and provide insights into the function of p110δ in the immune process (PMID: 30093657, 30194267, 30018075, 30738173).

In summary, PIK3CD is definitively associated with autosomal dominant immunodeficiency 14. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Antibody Deficiencies GCEP on April 19, 2022 (SOP Version 8).