A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing

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.