Reply to Migeon and Haisley-Royster

To the Editor:We thank Drs. Migeon and Haisley-Royster (1998 [in this issue])xFamilial skewed X inactivation and X-linked mutations: unbalanced X inactivation is a powerful means to ascertain X-linked genes that affect cell proliferation. Migeon, BR and Haisley-Royster, C. Am J Hum Genet. 1998; 62: 1555–1557Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all References)Migeon and Haisley-Royster (1998 [in this issue]) for their interest in our research. We are, however, a bit puzzled by their letter to the editor, since they write that they disagree with the interpretation of our results yet then restate what was already written in our previously published article (Pegoraro et al. 1997xFamilial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Pegoraro, E, Whitaker, J, Mowery-Rushton, P, Surti, U, Lanasa, M, and Hoffman, EP. Am J Hum Genet. 1997; 61: 160–170Abstract | Full Text PDF | PubMedSee all ReferencesPegoraro et al. 1997).The 50-member pedigree that we reported showed an X-linked dominant disorder with male lethality. There is no question of this fact, because we found a deletion mutation of Xq28 associated with skewed X inactivation and recurrent pregnancy loss (LOD = 6.92). The deletion included the factor VIII gene, yet there were no males from 50 females with factor VIII deficiency, again clearly proving that this family had an X-linked dominant disorder with male lethality.Drs. Migeon and Haisley-RoysterxFamilial skewed X inactivation and X-linked mutations: unbalanced X inactivation is a powerful means to ascertain X-linked genes that affect cell proliferation. Migeon, BR and Haisley-Royster, C. Am J Hum Genet. 1998; 62: 1555–1557Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all ReferencesMigeon and Haisley-Royster appear to wish to address two issues: (1) interpretation of the likely mechanisms that would cause X-inactivation skewing in the females in this family; and (2) transcriptional timing of the deleted gene or gene products in Xq28 and the observed effect on miscarriage detection. There is very little to disagree with in Drs. Migeon and Haisley-Royster'sxFamilial skewed X inactivation and X-linked mutations: unbalanced X inactivation is a powerful means to ascertain X-linked genes that affect cell proliferation. Migeon, BR and Haisley-Royster, C. Am J Hum Genet. 1998; 62: 1555–1557Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)See all ReferencesMigeon and Haisley-Royster's interpretation of our results; they suggest that a growth disadvantage is probably playing a role, which is precisely what we stated in our discussion. We, too, feel that growth disadvantage is the most likely mechanism causing skewing of X-chromosome inactivation. However, in the absence of characterization of the causative genes in Xq28, it seems unreasonable to dismiss the possibility that the gene(s) may actually be involved in the process of X inactivation. This is the least likely mechanism, but it does not seem to warrant exclusion from discussion.The timing of transcription of the gene products in Xq28 undoubtedly affects when the miscarriage occurs. In fact, the issue of timing is central to the inferred genetic mechanism. A cell-lethal trait expressed very early in embryonic development would be undetectable or perhaps would cause a “biochemical pregnancy.” Activation later in embryonic life would still cause male lethality but would be less likely to cause complete skewing of X inactivation in multiple tissues in the heterozygous female. In view of this delicate balance in timing, we feel that the genes in question are most likely to be transcribed early in fetal development and to impart a growth disadvantage rather than being cell lethal. The size of the deletion mutation, however, is less important to when the miscarriage occurs: size is simply being used as a surrogate to the assumed importance of the deletion region and gene(s) contained in that region. In the end, this is all an exercise in mental gymnastics, since the characterization of the causative gene(s) will enlighten us all as to the true mechanism.