Stephen C. Collins

Identification of Novel FMR1 Variants by Massively Parallel Sequencing in Developmentally Delayed Males

Fragile X syndrome (FXS), the most common inherited form of developmental delay, is typically caused by CGG‐repeat expansion in FMR1. However, little attention has been paid to sequence variants in FMR1. Through the use of pooled‐template massively parallel sequencing, we identified 130 novel FMR1 sequence variants in a population of 963 developmentally delayed males without CGG‐repeat expansion mutations. Among these, we identified a novel missense change, p.R138Q, which alters a conserved residue in the nuclear localization signal of FMRP. We have also identified three promoter mutations in this population, all of which significantly reduce in vitro levels of FMR1 transcription. Additionally, we identified 10 noncoding variants of possible functional significance in the introns and 3′‐untranslated region of FMR1, including two predicted splice site mutations. These findings greatly expand the catalog of known FMR1 sequence variants and suggest that FMR1 sequence variants may represent an important cause of developmental delay.

Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype

Background Fragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract. Methodology/Principal Findings To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations. Conclusions/Significance These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.

Minireview: Metabolism of Female Reproduction: Regulatory Mechanisms and Clinical Implications

Female fertility is highly dependent on successful regulation of energy metabolism. Central processes in the hypothalamus monitor the metabolic state of the organism and, together with metabolic hormones, drive the peripheral availability of energy for cellular functions. In the ovary, the oocyte and neighboring somatic cells of the follicle work in unison to achieve successful metabolism of carbohydrates, amino acids, and lipids. Metabolic disturbances such as anorexia nervosa, obesity, and diabetes mellitus have clinically important consequences on human reproduction. In this article, we review the metabolic determinants of female reproduction and their role in infertility.

Preimplantation genetic diagnosis: technical advances and expanding applications.

Purpose of review To review the foundations, recent technical advances, and increasing number of applications for in-vitro fertilization with preimplantation genetic diagnosis (PGD). Recent findings PGD is an important technique for reducing the burden of genetic disease. Studies have shown that the diagnostic accuracy and subsequent live-birth rate after PGD are impacted by the developmental stage at the time of biopsy, as well as the biopsy protocol used. Also essential for accurate diagnosis are refined mutation detection protocols which avoid the common problem of allele drop-out. As the technique has improved, there has been a concomitant increase in the popularity and breadth of application of PGD. A recently published 10-year dataset of worldwide PGD reveals the increasing frequency of its use and the growing number of indications for which PGD is offered. Summary Technical advances from biopsy to detection of mutations have led to improved diagnostic accuracy and an increased frequency and breadth of use for PGD.

Cost-effectiveness of preimplantation genetic screening for women older than 37 undergoing in vitro fertilization

PurposeAdding preimplantation genetic screening to in vitro fertilization has been shown to increase live birth rate in women older than 37. However, preimplantation genetic screening is an expensive procedure. Information on the cost-effectiveness of preimplantation genetic screening can help inform clinical decision making.MethodsWe constructed a decision analytic model for a hypothetical fresh, autologous in vitro fertilization cycle (with versus without preimplantation genetic screening) for women older than age 37 who had a successful oocyte retrieval and development of at least one blastocyst. The model incorporated probability and cost estimates of relevant clinical events based on data from published literature. Sensitivity analyses were performed to examine the impact of changes in model input parameters.ResultsIn base-case analysis, IVF-PGS offered a 4.2 percentage point increase in live birth rate for an additional cost of

Precision reproductive medicine: multigene panel testing for infertility risk assessment

4509, yielding an incremental cost-effectiveness ratio (ICER) of

Racial and Ethnic Differences in the Utilization of Prayer and Clergy Counseling by Infertile US Women Desiring Pregnancy

105,489 per additional live birth. This ICER was below the expected cost of

Women's career priority is associated with attitudes towards family planning and ethical acceptance of reproductive technologies

145,063 for achieving one live birth with IVF (assuming an average LBR of 13.4% and

Sociocultural determinants of US women's ethical views on various fertility treatments

19,415 per cycle for this patient population). Sensitivity analysis suggested that ICER improved substantially with decreases in PGS cost and increases in PGS effectiveness. Monte Carlo simulation showed PGS to be cost-effective in 93.9% of iterations at an acceptability cutoff of

Cost-effectiveness of Preimplantation Genetic Screening for Women Older than 37 Years Undergoing IVF [19P]

145,063.ConclusionsConsidering the expected cost of achieving one live birth with IVF, PGS is a cost-effective strategy for women older than 37 undergoing IVF. Additional research on patients’ willingness-to-pay per live birth would further inform our understanding regarding the cost-effectiveness of PGS.