Protein kinase C delta (PRKCD) was first reported in relation to autosomal recessive systemic lupus erythematosus (SLE) in 2013 (Belot et al, PMID: 23666743). Clinical reports have described affected individuals as having SLE, SLE-like, ALPS, ALPS-like, or CVID-like disease. While there is variability in severity of phenotype, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no significant difference in molecular mechanism(s) or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity: Autoimmune lymphoproliferative syndrome, type III (OMIM:615559), and systemic lupus erythematosus (MONDO ID: 0007915).
Eleven variants (2 nonsense, 2 frameshift, 3 splicing, and 5 missense) have been reported in 10 probands in 8 publications (PMIDs: 23666743, 28003329, 34264265, 36650346, 26233237, 23319571, 23430113, 33047643) which are included in this curation. Of these ten probands, all had family members tested which confirmed segregation of the PRKCD variant with disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function.
This gene-disease relationship is also supported by experimental evidence including animal models, expression studies, and in vitro functional assays (PMIDs: 23666743, 11976687, 23430113), all of which demonstrated that variants in PRKCD result in partial or complete loss of expression, reduced phosphorylation activity, and recapitulate human immune phenotypes in mice and patient cells. PRKCD mutant lymphoblastoid cell lines are resistant to apoptosis, but are rescued by coexpression of wild type protein. There is additional experimental evidence in Neehus et al. 2021 (PMID: 34264265), which was not included because the overall classification has reached the definitive level.
In summary, there is definitive evidence supporting the relationship between PRKCD and autosomal recessive systemic lupus erythematosus. 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 Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date October 11, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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