The purpose of the workshop was to discuss the current scientific knowledge and to stimulate research interest, as well as collaboration, by the scientific community in a poorly developed area involving genetic factors that affect pregnancy outcome.
The topics to be covered included genomic imprinting, confined placental mosiacism (CPM), and uniparental disomy (UPD) as they relate to fetal growth and their impact later in life. The basic science and clinical aspects underlying these topics were presented and potential future directions in research discussed.
Recent progress in genetics has revealed that for specific genes only one of the two alleles is active, depending on the parental origin. This phenomenon is known as genomic imprinting. Genomic imprinting sheds new light on some of the underlying mechanisms of intrauterine growth. Animal studies have shown that maternal genes are necessary for the development of the embryo, while paternal genes are necessary for placental development. Furthermore, studies using mice that were genetically engineered to carry well-defined chromosomal fragments derived from a single parent (called UPD) allowed the localization of an imprinted gene based on an abnormal phenotype. The resultant phenotypes commonly ranged from early to late fetal death or fetuses that were growth restricted, indicating the importance of imprinted genes in fetal development. Although the chromosomal location of imprinted genes that affect fetal development have been mapped in the mouse, most of the specific genes and their corresponding human homologues have yet to be identified. Stimulating research in this area is needed to identify these genes and their mechanism of action to better understand the factors involved in fetal growth.
CPM is a chromosomal abnormality (most often a trisomy) that is present intermittently in the placenta, but not the fetus. It occurs at a frequency of 1-2/100 pregnancies, with approximately 22 percent of these pregnancies resulting in spontaneous abortions, intrauterine growth restriction (IUGR), intrauterine death or perinatal morbidity. The workshop focused primarily on the role of CPM in IUGR, an important clinical problem because IUGR affects 6/100 of all pregnancies and CPM is associated with 20 percent of idiopathic IUGR. Little is known on how the degree and spatial location(s) of mosaicism in the placenta affects fetal viability and well-being. Furthermore, little is known on what genes on the affected chromosome(s) are responsible for the clinical condition. More research in this area will provide the opportunity to identify important genes that affects placental development and impacts fetal growth.
In human fetuses, partial or complete UPD of most chromosomes have been reported. In a few instances, certain chromosomal UPDs are associated with abnormal intrauterine growth, mostly growth restriction. Most chromosomal UPDs are thought to be benign, unless they carry an imprinted gene or recessive disorder. This notion is based, however, on anecdotal evidence using case reports or very small sample sizes with generally incomplete clinical evaluation or follow-up. Furthermore, because some imprinted genes are not universally expressed, but rather, their expression is confined to specific cell types and/or stage of development, the phenotypic consequence of a chromosomal UPD may not be initially obvious, hence eluding detection, only to manifest itself later in life. Stimulating research in this area is particularly underscored because of the postulated high incidence of this genetic anomaly in the general population. Calculations based on the frequency of a chromosomal UDP associated with chromosome 15 suggest that the incidence of UDP for any one chromosome can be as high as 1/3500 live births. Additionally, because aneuploidy for most chromosomes increases dramatically with maternal age, chromosomal UPD may be particularly high in the offspring of women at later childbearing ages. Based on similar calculations, a UPD for any one chromosome can be estimated to occur at a frequency of 1/150 live births for women over the age of 40. Thus, research in this area needs to be stimulated to clearly determine which chromosomal UPDs are actually benign, and what chromosomal UPDs can exert subtle, but detrimental, effects on the fetus or possibly later in life.