title: Estimate of de novo mutation frequency in probands with PTEN hamartoma tumor syndrome.
abstract: OBJECTIVE
  PTEN hamartoma tumor syndrome is an autosomal dominant disorder with increased risks of neoplasias, macrocephaly, and developmental disabilities. While both familial and sporadic cases exist, actual de novo mutation frequency remains unknown. We sought to estimate this within our PTEN-mutation positive patient series.
  
  
  METHODS
  Patients were prospectively accrued if they had known pathogenic germline PTEN mutations or phenotypic features suspicious for PHTS. Only families with pathogenic PTEN mutations were included. Likelihood for de novo mutation was graded from 1 (confirmed inherited) to 5 (confirmed de novo) based on family history and mutation status. Fisher's two-tailed exact and unpaired t-tests were used to compare between groups.
  
  
  RESULTS
  187 pathogenic PTEN-mutation positive families were eligible for this study. De novo (grade 5) status was confirmed in 20 (10.7%) probands, and in 36 (19.3%) was suspected based on family history. Demographics, mutations, and phenotypes were similar for probands graded 1 vs. 5 (all P > 0.06). In grade 1 probands, mutations were inherited equally from maternal and paternal lineages (P = 0.55).
  
  
  CONCLUSIONS
  The frequency of de novo PTEN mutation is at minimum 10.7% and at best 47.6%. Absence of PHTS features within a family history should not preclude consideration of this diagnosis for patients with relevant personal history.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mester
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005799:Genes, Dominant; D006223:Hamartoma Syndrome, Multiple / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011336:Probability
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human