Post-zygotic mutations and somatic mosaicism in androgen insensitivity syndrome

Abstract

Holterhus et al. (this issue) correctly point out that we did indeed misinterpret part of their results concerning the possibility that some cases of androgen insensitivity syndrome (AIS) could be due to somatic mosaicism caused by the back mutation of mutant androgen receptors to wild-type in some androgen responsive tissues. However, although back mutations have not yet been proven to be a source of somatic mosaicism in cases of AIS, there are a number of other cases in the literature where back mutations do indeed result in somatic mosaicism1xReverse mutations – spontaneous amelioration or cure of inherited disorders?. Wahn, V. et al. Eur. J. Pediatr. 1998; 157: 613–617Crossref | PubMed | Scopus (6)See all References, 2xRevertant mosaicism in human genetic disorders. Jonkman, M.F. Am. J. Med. Genet. 1999; 85: 361–364Crossref | PubMed | Scopus (34)See all References, 3xBack mutations can produce phenotype reversion in Bloom syndrome somatic cells. Ellis, N.A. et al. Hum. Genet. 2001; 108: 167–173Crossref | PubMed | Scopus (20)See all References.We are also grateful that they chose to reinforce the importance of such information for genetic counseling, particularly because the occurrence of somatic mosaicism has recently been shown to be more than just an isolated series of events in a number of genetic disorders. In these conditions, which include hemophilia A (Ref. 4xSomatic mosaicism in Hemophilia A: a fairly common event. Leuer, M. et al. Am. J. Hum. Genet. 2001; 69: 75–87Abstract | Full Text | Full Text PDF | PubMed | Scopus (83)See all ReferencesRef. 4), hemophilia B (Ref. 5xGermline origins in the human F9 gene: frequent G:C(A:T mosaicism and increased mutations with advanced maternal age. Ketterling, R.P. et al. Hum. Genet. 1999; 105: 629–640Crossref | PubMed | Scopus (30)See all ReferencesRef. 5), retinoblastoma6xFrequency of somatic and germ-line mosaicism in Retinoblastoma: implications for genetic counseling. Sippel, K.C. et al. Am. J. Hum. Genet. 1998; 62: 610–619Abstract | Full Text | Full Text PDF | PubMed | Scopus (106)See all References6 and tuberous sclerosis complex7xHigh rate of mosaicism in tuberous sclerosis complex. Verhoef, S. et al. Am. J. Hum. Genet. 1999; 64: 1632–1637Abstract | Full Text | Full Text PDF | PubMed | Scopus (99)See all References7, somatic mosaicism can occur at a frequency of 10–20%. Furthermore, these studies also note that somatic mosaicism is a possible source not only of variable expressivity, but also of altered penetrance.These observations add weight to our hypothesis that, with the recently acquired ability to sequence specific tissues easily and efficiently, somatic mosaicism is increasingly likely to be observed as a source of variable expressivity in many disorders and diseases.