Submission Details

POLA1 was first reported in relation to an X-linked POLA1 deficiency in 2016 (Starokadomskyy, et al., 2016, PMID:27019227). Symptoms usually appear in infancy (first few months to first few years) and most male patients present diffuse skin hyperpigmentation with distinctive reticular pattern, characteristic facial features with frontally upswept hair and flared eyebrows, recurrent lung infections, failure to thrive and hypohidrosis. Corneal inflammation and photophobia are also present in most cases. Female carriers only have restricted pigmentary changes along Blaschko's lines but no other health issues. Patients have normal numbers of T and B cells but reduced number of NK cells. All cases reported were hemizygous for the same hypomorphic mutation that created a splice donor site in intron 13 (NM_001330360.2(POLA1):c.1393-354A>G), leading to 60-65% of transcripts being aberrant and unstable. This mutation leads to the expression of POLA1 at very low levels. The curation of POLA1 relates to X-linked pigmentary reticulate disorder (XLPDR) with MONDO ID 0010523 includes both case-level and experimental evidence. The first publication described a large Canadian family with several family members presenting skin pigmentation features and several male members of the family presenting the disease symptoms (PMID: 6794369 and 2705473). At the time, no genetic mutation was known. Several other cases were reported in other populations (PMIDs: 8302737, 15804299, 23613254, 18365917, 27019227) before the mutation was found and a few more after that (PMIDs: 32989594, 35645674, 37851432) and the mutation in intron 13 of POLA1 was confirmed in all cases. A score of 3.25 points for genetic evidence has been reached. This gene-disease association is also supported by expression, functional alteration, model systems, protein interaction and rescue models (PMIDs: 27019227 and 31672938). Protein expression in dermal fibroblasts from patients is markedly reduced a as well as wild-type mRNA levels. The misspliced POLA1 mRNA is also present at low levels, suggesting it is unstable and degrades. Also, HEK293 cells transfected with a fragment of POLA1 containing exon 13–14 and flanking sequences from control or XLPDR genomic DNA lead to two transcripts and the larger transcript sequencing confirmed presence of ex13a. Patient cells and other cells containing mutant POLA1 or silenced using siPOLA1 showed a marked decrease in the expression of MCM and and GINS proteins, which are present at the replication fork and immunoprecipitation confirmed physical interaction between POLA1 and PRIM2 and MCM4. Patients with XLPDR have lower total number and proportion of NK cells and these exhibited lower cytotoxic activity than the controls and impaired mobilization of lytic granules. The NK cells of patients also had impaired maturation, exhibiting a reduced number of mature NK cells. Patient cells also showed constitutive activation of IRF- and NF-κB-dependent genes, which resulted in a strong type I interferon response in patients with XLPDR. Patients' cells had almost undetectable cytosolic DNA-RNA hybrids and that phenotype was rescued when patient cells were transfected with WT POLA1. A score of 5 points for experimental evidence has been reached, increasing the total score to 8.25 points. In summary, POLA1 is moderately associated with XLPDR. More cases and research will be needed to elevate the classification to strong. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date February 20, 2025 (SOP Version 11).