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Broadening our lens: Investigating the frequency of xeroderma pigmentosum by mining genomic databases

Wednesday, September 13, 2017 — Poster Session II

3:30 p.m. – 5:00 p.m.
FAES Terrace


  • JM Pugh
  • SG Khan
  • D Tamura
  • A Goldstein
  • JJ DiGiovanna
  • KH Kraemer


Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in genes involved in the nucleotide excision repair (NER) pathway including XPA-XPG and POLH. Patients with XP are unable to repair UV induced DNA damage, increasing their risk for skin cancer by 10,000-fold. We sought to identity all known XP causing mutations by searching the patients evaluated at NIH and those reported in the Human Gene Mutation Database (HGMD). We identified 161 XP associated missense mutations. Since the prevalence of XP is estimated to be one in a million, we hypothesized that the frequencies of these mutations would reflect the previously reported estimate. We analyzed the allele frequencies of these mutations in the general population using the gnomad database which has exome sequences of 123, 000 people from 7 different populations in the world. We found that XP causing mutations had a frequency of 1.22% and that 6 mutations harbored over 50% of the total frequency of XP causing mutations. While XPF only accounts for 1.6% of all reported cases of XP, it harbored the most frequent mutations, p. P379S and p. R799W, with frequencies of 4.05E-3 and 4.53E-4, respectively. The frequency of XPF p.P379S yielded a predicted 11,782 affected homozygous patients with this mutation alone. Conversely, there were only 3 patients with XPF p. P379S reported in the literature, and they had only minimum skin involvement. The number of reported XP-F patients might be fewer than expected if the phenotype is very mild or difficult to diagnose or, conversely, very severe with death in utero. There may also be other modifying genes that prevent full expression of the XP phenotype. Alternatively, these patients may have a varied phenotype without increased cancer risks and late onset neurodegeneration. These findings imply a discordance between the frequency of genotype and identified phenotype, and suggest that the clinical spectrum of XP is broader than currently understood.

Category: Genetics and Genomics