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Background DNA repair deficiency disorders are rare inherited diseases arising from pathogenic (disease-causing) variants in genes involved in DNA repair. There are no standardized diagnostic assays for the investigation of pathological significance of unknown variants in DNA repair genes. We hypothesized that our assays for measuring in vitro patient blood cell hypersensitivity to DNA-damaging agents can be used to establish the pathological significance of unknown variants in DNA repair genes. Six patients with variants in the DNA repair genes  PRKDC  (two siblings),  DCLRE1C  (two siblings),  NBN , and  MSH6  were included. Here, we used the cell division assay (CDA) and the γ-H2AX assay, which were both developed and clinically validated by us, to measure patient cell hypersensitivity in response to ionizing radiation, mitomycin C, cytarabine and doxorubicin. Results Radiation hypersensitivity was detected in the two patients with variants in the  PRKDC  gene ( p  &lt; 0.0001 for both at 3.5 Gy), and the two patients with  DCLRE1C variants  ( p  &lt; 0.0001 at 3.5 Gy for sibling 1 and  p  &lt; 0.0001 at 1 Gy for sibling 2). The cells from the patients with the  PRKDC  variant were also deficient in removing γ-H2AX ( p  &lt; 0.001). The cells from the patient with variants in the  NBN  gene were hypersensitive to mitomycin C ( p  = 0.0008) and deficient in both induction and removal of γ-H2AX in response to radiation. Conclusions The combination of the CDA and the γ-H2AX assay is useful in investigating the significance of unknown variants in some DNA repair genes.

Clinical measurement of cellular DNA damage hypersensitivity in patients with DNA repair defects