A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing

Genet Med. 2013 Dec;15(12):1004-7. doi: 10.1038/gim.2013.51. Epub 2013 Apr 25.

Abstract

Purpose: Mosaic PTEN mutations are not well described in Cowden syndrome. We report a 40-year-old woman with a clinical diagnosis of Cowden syndrome including Lhermitte-Duclos disease, who had a mosaic PTEN mutation detected by next-generation deep sequencing.

Methods: Complete PTEN gene sequencing by the Sanger method and deletion/duplication analysis performed on DNA extracted from blood leukocytes at a commercial clinical laboratory did not identify a mutation. Because of high suspicion of a PTEN mutation, we repeated testing by next-generation sequencing using the ColoSeq assay, which sequences the entire PTEN locus at >320-fold average coverage.

Results: ColoSeq identified a frameshift PTEN mutation (c.767_768delAG) in 1.7% of sequencing reads from peripheral blood leukocytes (21/1,184 reads), which is below the limit of detection of most Sanger sequencing methods. The mutation was detected at full heterozygous levels in skin fibroblasts and a cerebellar tumor, and at approximately the 25% level in colonic and endocervical mucosa, confirming somatic mosaicism.

Conclusion: Our report highlights the power of deep next-generation sequencing to identify mosaic mutations that can be missed by traditional less sensitive approaches. We speculate that mosaic PTEN mutations are more common in Cowden syndrome than previously described.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Cells, Cultured
  • Cerebellar Neoplasms / genetics*
  • Female
  • Frameshift Mutation*
  • Hamartoma Syndrome, Multiple / genetics*
  • Heterozygote
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Mosaicism
  • PTEN Phosphohydrolase / genetics*

Substances

  • PTEN Phosphohydrolase
  • PTEN protein, human