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: Vanessa Barbaro, Paola Nardiello, Giuseppe Castaldo, Colin E Willoughby, Stefano Ferrari, Diego Ponzin, Felice Amato, Ernesto Bonifazi, Mohit Parekh, Arianna Calistri, Cristina Parolin, Enzo Di Iorio
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 158A Issue 8 Pg. 1957-61 (Aug 2012) ISSN: 1552-4833 [Electronic] United States
• PMID: 22740388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins

Topics

• Amino Acid Sequence
• Cleft Lip (diagnosis, genetics)
• Cleft Palate (diagnosis, genetics)
• Female
• Germ Cells
• Humans
• Male
• Molecular Sequence Data
• Mosaicism
• Mutation, Missense
• Pedigree
• Prenatal Diagnosis
• Sequence Homology, Amino Acid
• Syndrome
• Transcription Factors (chemistry, genetics)
• Tumor Suppressor Proteins (chemistry, genetics)