PTEN Hamartoma Tumor Syndrome via the PTEN Gene

PTEN hamartoma tumor syndrome (PHTS) is a cluster of related clinical conditions, all caused by germline variants in the PTEN tumor suppressor gene (OMIM 601728). Included in PHTS are Cowden syndrome (CS; OMIM 158350), Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM 153480), Proteus (PS; OMIM 176920) and Proteus-like syndromes, and VACTERL association with hydrocephalus (OMIM 276950). While each PHTS condition has its own unique pathognomonic features (see for example Blumenthal & Dennis, Eur J Hum Genet 16:1289-1300, 2008), hamartomatous overgrowth, macrocephaly, and vascular malformations appear to be common to all conditions (Zhou et al. Lancet 358:210-211, 2001). A presumptive diagnosis of PHTS is typically made based on clinical symptoms, but a definitive diagnosis requires the identification of a heterozygous PTEN variant. Patients with a germline variant in PTEN have a 5-10 fold higher chance of developing cancer at a much earlier age (<30 years old) than the general population (Eng, Hum Mut 22:183-198, 2003). In addition to confirming the diagnosis of PHTS, testing patients for a germline PTEN variant is essential to accurately assess their risk for cancer and to make appropriate recommendations regarding prevention and treatment of malignancy.

PTEN hamartoma tumor syndrome inherited in an autosomal dominant manner, and PTEN is the only known gene to be associated with the disease. In addition to PHTS, germline variants in PTEN have been identified in 16% of patients with autism spectrum disorders (ASD) and macrocephaly, 12.5% of patients with adenomatous and hyperplastic polyps, and 5% of women with at least two different types of cancer (Zbuk & Eng Nat Rev Cancer 7:35-45, 2007; Lintas & Persico J Med Genet 46:1-8, 2009). To date, ~230 variants have been reported for the PTEN gene, and most (~95%) are detectable by DNA sequencing (Human Gene Mutation Database, www.hgmd.cf.ac.uk). The PTEN gene consists of 9 exons and encodes a dual lipid and protein phosphatase. Variants have been reported throughout the coding region, and sequencing of all 9 exons is recommended (Eng Hum Mut 22:183-198, 2003). Five variants have also been reported within the minimal promoter about 800 bp upstream of the start codon and sequencing of this region is also recommended (Teresi et al. Am J Hum Genet 81:756-767, 2007).

This test is predicted to detect causative variants in ~80% of patients with CS, ~65% of patients with BRRS, and ~20% of patients with PS (Eng Hum Mutat 22:183-198, 2003).

This test provides full coverage of all coding exons of the PTEN gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

In addition to the regions described above, this testing includes coverage of the PTEN minimal promoter region (positions -1239 to -765 relative to the start codon).