De novo copy number variants and parental age: Is there an association?

PURPOSE: To investigate whether increased parental age is associated with an increased risk for de novo copy number variant (CNV) formation in offspring. METHODS: CNV calls from 2323 individuals referred to Signature Genomic Laboratories for clinical microarray-based comparative genomic hybridization were investigated; 17% of the samples were prenatal and 83% were postnatal. The de novo CNV data were further split into de novo CNVs bound by low copy repeats (LCRs) and those not bound by LCRs. RESULTS: No association was found between CNV occurrence and paternal age in both the prenatal (p = 0.6795) and postnatal (p = 0.1741) cohorts. Maternal age was significantly higher with de novo CNV occurrence in our postnatal cohort (p = 0.0126), an effect which may be driven by formation of de novo CNVs that are bound by LCRs (p = 0.0026). Furthermore, a significant positive correlation was observed between maternal age and de novo CNVs (Point-Biserial R2 = 0.0503, p = 0.0152). CONCLUSIONS: This large-scale study did not find any evidence for the influence of increased paternal age on de novo CNV formation, while increased maternal age appeared to increase risk for de novo, non-complex CNV occurrence in offspring with intellectual disability/developmental delay. Further studies and continued technological advances will help yield more information on the risk factors for de novo CNVs.

Discussion: 'Add-back regimens in patients using a GnRH agonist for premenstrual dysphoric disorder' by Segebladh et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Segebladh B, Borgström A, Nyberg S, et al. Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder. Am J Obstet Gynecol 2009;201:139.e1-8.

Facilitative glucose transporter type 1 is differentially regulated by progesterone and estrogen in murine and human endometrial stromal cells.

Embryo implantation is a highly synchronized event between an activated blastocyst and a receptive endometrium. The success of this process relies on the dynamic interplay of estrogen (E(2)) and progesterone (P(4)), however, the details of this interaction are not entirely clear. Recent data implicate E(2) and P(4) in the regulation of glucose utilization by affecting facilitative glucose transporter (GLUT) expression. In this study we examine GLUT1 expression in murine and human endometrial stromal cells (ESCs) using a primary culture system. We show that expression of GLUT1 is increased during ESC decidualization in vitro. P(4) up-regulates, whereas E(2) down-regulates, GLUT1 expression. In addition, P(4) increases and E(2) decreases glucose uptake in ESCs, suggesting that GLUT1 may be a major player in glucose utilization in these cells. Moreover, GLUT1 expression is increased in human ESCs when decidualized in vitro with P(4) and dibutyryl cAMP, suggesting a similar role for P(4) in human endometrium. In conclusion, an imbalance between P(4) and E(2) seen in patients with polycystic ovary syndrome, luteal phase defect, and recurrent pregnancy loss may have a critical impact on glucose utilization in the endometrial stroma, and, thus, may be responsible for endometrial dysfunction and failure of embryo implantation in these patient populations.