Daughters Get Retts an X-linked Dominant Disorder Because Daughters Receive the X Chromosome With The Dominant Mutation From Their Fathers ?
1: Am J Hum Genet. 1996 Jun;58(6):1364-8. Links
High male:female ratio of germ-line mutations: an alternative explanation for postulated gestational lethality in males in X-linked dominant disorders.Thomas GH.
Department of Pediatrics, The John Hopkins University School of Medicine, Baltimore, MD, USA
In this paper I suggest that a vastly higher rate of de novo mutations in males than in females would explain some, if not most, X-linked dominant disorders associated with a low incidence of affected males. It is the inclusion of the impact of a high ratio of male:female de novo germ-line mutations that makes this model new and unique. Specifically, it is concluded that, if an X-linked disorder results in a dominant phenotype with a significant reproductive disadvantage (genetic lethality), affected females will, in virtually all cases, arise from de novo germ-line mutations inherited from their fathers rather than from their mothers. Under this hypothesis, the absence of affected males is explained by the simple fact that sons do not inherit their X chromosome (normal or abnormal) from their fathers. Because females who are heterozygous for a dominant disorder will be clinically affected and will, in most cases, either be infertile or lack reproductive opportunities, the mutant gene will not be transmitted by them to the next generation (i.e., it will be a genetic lethal). This, not gestational lethality in males, may explain the absence of affected males in most, if not all, of the 13 known X-linked dominant diseases characterized by high ratios of affected female to male individuals. Evidence suggesting that this mechanism could explain the findings in the Rett syndrome is reviewed in detail.
PMID: 8651313 [PubMed - indexed for MEDLINE
For one thing, Rett syndrome occurs sporadically more than 99% of the time
HERE IS THE ANSWER ONE MAN TWO DAUGHTERS WITH DIFFERENT MOTHERS BOTH DAUGHTERS WITH RETTS "WE SHOW THAT THE MUTATION IS PRESENT AT A LOW LEVEL IN THE DNA EXTRACT FROM THE FATHER'S(PATIENT'S) SPERM"
Clin Genet. 2006 Oct;70(4):336-8.
Germline mosaicism for a MECP2 mutation in a man with two Rett daughters
Evans JC, Archer HL, Whatley SD, Clarke A.
Department of Medical Genetics, Cardiff University, Cardiff, UK.
Rett syndrome is a severe neurodevelopmental disorder that is caused by mutations in the X-linked gene, methyl-CpG binding protein 2 (MECP2). The majority of cases are sporadic, but rarely germline mosaicism can lead to familial cases. Here, we report the first case where germline mosaicism for a MECP2 mutation has been shown in a man. He has two affected daughters who are half sisters, and both have the c.808delC mutation. We show that this mutation is present at a low level in DNA extracted from the patient's semen. This case has implications for genetic counseling, and pre-natal testing should be offered for the partners of men who have a daughter with Rett syndrome.
The vast majority of MeCP2 mutations in Rett Syndrome are sporadic mutations – that is, they are novel mutations. However, a few familial Rett Syndrome cases have been reported. In four cases, the mother was a non-symptomatic carrier; in four other cases, a “germline mosaicism” in the mother was hypothesized. That is, in a “germline mosaicism” only the germline cells (sperm, eggs) possess the mutation, and not the other cells of the body. In this study, the authors describe the first case of a germline mosaicism for Rett Syndrome in a man. Specifically, this case study describes a father with two daughters with Rett Syndrome, from two different mothers. Despite having different mothers, it was found that the Rett daughters share the similar uncommon MeCP2 mutation. Further genetic testing revealed that the mutation had been transmitted from the father’s germline – the mutation was present in DNA extracted from his sperm. As a result, the authors suggest that genetic counselling and prenatal testing should be available for men with an affected child.