title: A novel de novo missense mutation in TP63 underlying germline mosaicism in AEC syndrome: implications for recurrence risk and prenatal diagnosis.
abstract: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant ectodermal dysplasia syndrome. It is caused by heterozygous mutations in TP63, encoding a transcriptional factor of the p53 family. Mutations in TP63, mainly missense in exons 13 and 14 encoding the sterile alpha motif (SAM) and the transactivation inhibitory (TI) domains, account for 99% of mutations in individuals with AEC syndrome. Of these, ≥70% are de novo mutations, present in the affected patient, but not in parents nor in healthy siblings. However, when a mutation appears de novo, it is not possible to differentiate between a sporadic mutation, or germline mosaicism in the parents. In this latter case, there is a risk of having additional affected offspring. We describe two sisters with AEC syndrome, whose parents were unaffected. Both patients carried the heterozygous c.1568T>C substitution in exon 13 of TP63, resulting in a p.L523P change in the SAM domain of the protein. Analyses of DNA from parental blood cells, seminal fluid (from the father) and maternal cells (buccal, vaginal, and cervical) did not reveal the mutation, suggesting that the mosaicism may involve a very low percentage of cells (very low grade somatic mosaicism) or, more likely, maternal gonadal mosaicism. Mosaicism must be considered for the assessment of recurrence risk during genetic counseling in AEC syndrome, and pre-implantation/prenatal genetic diagnosis should be offered to all couples, even when the mutation is apparently de novo.
authors: The Veneto Eye Bank Foundation, Venice, Italy.
authors: Vanessa
authors: V
authors: Barbaro
authors: Paola
authors: P
authors: Nardiello
authors: Giuseppe
authors: G
authors: Castaldo
authors: Colin E
authors: CE
authors: Willoughby
authors: Stefano
authors: S
authors: Ferrari
authors: Diego
authors: D
authors: Ponzin
authors: Felice
authors: F
authors: Amato
authors: Ernesto
authors: E
authors: Bonifazi
authors: Mohit
authors: M
authors: Parekh
authors: Arianna
authors: A
authors: Calistri
authors: Cristina
authors: C
authors: Parolin
authors: Enzo
authors: E
authors: Di Iorio
mesh_terms: D000595:Amino Acid Sequence; D002971:Cleft Lip / Q000175:diagnosis* / Q000235:genetics; D002972:Cleft Palate / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005854:Germ Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D020125:Mutation, Missense; D010375:Pedigree; D011296:Prenatal Diagnosis; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins