Submission Details

PRKDC was first reported in relation to autosomal recessive combined immunodeficiency due to DNA-PKcs deficiency in 2009 (van der Burg et al., PMID: 1907532). The phenotype of patients with DNA-PKcs deficiency can be variable but may include: a spectrum of combined immunodeficiency, recurrent infections, progressive pulmonary disease, growth retardation, dysmorphic facies, neurologic abnormalities, and autoimmunity. PRKDC encodes the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase (DNA-PK) which is involved in NHEJ during DNA double-strand break (DSB) repair and for V(D)J recombination during immune development. Patients with hypomorphic mutations, with partially preserved T and B cell development, can present with signs of autoimmunity owing to the role of DNA-PKcs in regulating expression of AutoImmune-Regulator (AIRE)-dependent peripheral tissue antigens during thymocyte selection. It is a rare inborn error of immunity. Thus far, pathogenic missense variations and splicing abnormalities have been reported in several publications (PMIDs: 19075392, 23722905, 30121298, 25842288, 26546606, 26122175, 30778343, 29921932) and many are included in this curation. Nonsense or frameshift variants have not yet been described in humans. The mechanism of pathogenicity is reported to be hypomorphic loss of function. Heterozygous carriers have not been shown to have a clinical phenotype. This gene-disease association is also supported by accompanying experimental evidence in both PRKDC-deficient patients (PMIDs 19075392, 23722905, 26546606). and animal models (PMIDs 8524788, 11489998, 22981234, 27566103). In summary, PRKDC is definitively associated with autosomal recessive combined immunodeficiency due to DNA-PKcs deficiency. 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 SCID/CID GCEP on November 18, 2021 (SOP Version 8).