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 into separate curations. Roifman-Chitayat syndrome (613328) is split as well, but not curated due to digenic inheritance.

The relationship between PIK3CD and immunodeficiency 14B, an autosomal recessive 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 14b is characterized by recurrent infections, hypogammaglobulinemia, IBD, low-normal B cell levels, normal NK and T cells, impaired cellular cytotoxic immunity and defective T-cell function.

PIK3CD was first reported in relation to autosomal recessive immunodeficiency 14b in 2018 by Sogkas et al (PMID: 30040974). Only a few pathogenic LOF variants have been reported in humans in the ClinVar database. The PIK3CD gene is highly constrained for pLOF variation (o/e = 0.09, gnomAD v2.1.1). Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (11 points): Variants in this gene have been reported in at least 3 probands in 3 publications (PMID: 30336224, 30040974, 31073077). An additional proband published in an abstract [Zhang KJ, Husami A, Marsh R, Jordan MB. Identification of a phos-phoinositide-3 kinase (PI-3K) p110d (PIK3CD) deficient individual. J Clin Immunol. 2013;33:673-674] has been reported with hypogammaglobulinemia, sinopulmonary infections, septic arthritis, mild IBD as well as near absence of peripheral B cells and moderate T lymphopenia. This proband was found to carry a de novo in-frame deletion within the catalytic domain and a nonsense variant, inherited from the father. The PIK3CD protein expression was near absent. The evidence cannot be logged in the GCI, but warrants 2 points.

The mechanism of disease is loss of function. A proband with a multi-system disorder with biallelic variants in PIK3CD (Gln721Ter) in addition to biallelic variants in KNSTRN (PMID: 29180244) as well as another with biallelic variants in PIK3CD (Arg821His) and TNFRSF9 (PMID: 31537641) are reported in the literature. However, these probands are not scored due to digenic inheritance. Approximately 5% of inborn errors of immunity are currently considered to be related to digenic defects. In these two examples related to PIK3CD, epistatic interactions are revealed in new or blended phenotypes. This maybe relevant to future studies on epistasis and its impact on IEI diseases and phenotypes (PMID: 29434582).

Summary of experimental data (3.5 points): This gene-disease association is supported by in vitro functional assays and animal models. PIK3CD is predominantly expressed in leukocytes (PMID: 9235916). Knock out mouse models have been reported in the literature that recapitulate some of the phenotype (PMID: 12130661, 12235209).

In summary, PIK3CD is definitively associated with autosomal recessive immunodeficiency 14b. 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).