Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-09-22
2001-07-31
Jones, W. Gary (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S006120, C435S091100, C435S091200, C424S093200, C436S811000
Reexamination Certificate
active
06268145
ABSTRACT:
SUBJECT OF THE INVENTION
The invention is concerned with a screening method for diagnosing the etiology of spontaneous pregnancy loss in women. More particularly, the inventive method involves the use of quantitative X chromosome inactivation analysis for the prediction of the presence of gene-linked recurrent spontaneous pregnancy loss.
BACKGROUND OF THE INVENTION
Recurrent spontaneous abortion (RSA) is a major health concern to women, affecting about 17% of couples wishing to have children. The diagnostic evaluation of RSA is extensive and complex, with many different etiologies, each causing a small proportion of the total cases. The etiologies can be grouped into five categories: anatomic, infectious, hormonal, immunological, and genetic, thereby requiring the collaborative efforts of many medical specialists. Despite such thorough (and expensive) diagnostic workups, it has been estimated that the specific cause for RSA remains unknown in 37-79% of affected women (Stephenson,
Fertil. Steril.
66:24 (1996)).
It has been assumed that a large portion of idiopathic RSA is genetic in origin. To date, however, the standard genetic evaluation consists solely of parental and abortus karyotyping. This identifies parental defects, such as balanced translocations that can cause RSA, and it ascertains fetal aneuploidy, a common cause of spontaneous abortion that intrinsically has little recurrence risk. As a result, the published total “genetic” contribution to RSA is essentiually the frequency of translocations in the cohort of women with RSA, which is only about 3%. This is quite likely an underestimation, as subcytogenetic defects are almost certainly a significant cause of RSA.
It is possible that either autosomal or X-linked recessive lethal traits could cause RSA. Identification of recessive lethal traits has been difficult, as heterozygous carriers of such traits would appear phenotypically normal. A subset of lethal traits may cause an increased frquency of spontaneous abortions in carriers, if the X-linked hemizygous trait produces a clinically detectable pregnancy. Extended pedigrees in which women exhibit spontaneous abortion are available, but are difficult to analyze, because of the high population prevalence of spontaneous abortion and the assumed extensive genetic and etiologic heterogeneity. Thus, a method for clinically ascertaining carriers of autosomal lethal defects for recurrent spontaneous pregnancy loss remains problematical, although higly desirable.
There have been many efforts to characterize single genes that may cause miscarriage. However, there are approximately 100,000 genes in the human genome, which makes the search for such a single gene an almost intractable problem.
The present inventors have investigated the possibility that carriers of X-linked recessive lethal traits for recurrent spontaneous abortion manifest the molecular phenotype of nonrandom (skewed) X chromosome inactivation, and have invented a screening test for identifying and diagnosing a subset of women with recurrent spontaneous abortions. The test is based on a quantitative determination of the frequency of skewed X chromosome inactivation. This novel test, which is described below, can identify a lethal defect in a significant percentage of all of the genes in a woman. In essence, the test allows many of the lethal gene defects in the human genome to be surveyed at one time.
SUMMARY OF THE INVENTION
The screening test method of the invention provides for the identification and establishment of the risk for women who carry an X-linked lethal gene which increases their risk of recurrent spontaneous pregnancy loss.
The inventive test involves the quantitative determination in female subjects of the frequency of highly nonrandom (skewed) X chromosome inactivation, compared to that of appropriate control women.
The inventive test method is performed on DNA extracted from readily available cells from subjects, including, but not limited to, peripheral blood leukocytes, oral mucosal cells, muscle biopsies, or any other appropriate tissue.
These and other aspects of the invention will become apparent by reference to the specification and claims below.
REFERENCES:
Lanasa et al Am J Hum Gen. 65(1):252-4 (Jul. 1999).
Pegoraro et al. Am J Hum Gen 61(1):160-70 (Jul. 1997).
Sangha et al., Am J Hum Gen 65:913-17 (1999).
Pegoraro et al. Am J Hum Gen, 54:989-1003 (1994).
Lanasa et al. Am J Hum Gen, 64: 934-38 (1999).
Hoffman Eric P.
Hogge W. Allen
Lanasa Mark C.
Blecher Melvin
Children's National Medical Center
Jones W. Gary
Taylor Janell E.
LandOfFree
Screening test for the lethal genetic trait of recurrent... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Screening test for the lethal genetic trait of recurrent..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Screening test for the lethal genetic trait of recurrent... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2487392