Genomic Imprinting and Assisted Reproduction: Is There Cause for Concern?
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Dr. Louise Wilkins-Haug, Department of Obstetrics & Gynecology, Division of Reproductive Genetics,Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
With the introduction of in vitro fertilization (IVF) more than 20 years ago, and the rapid assimilation of technologies such as intracytoplasmic sperm injection (ICSI) over the past decade, successful pregnancies through assisted reproduction are rising rapidly. Not unexpectedly, the number of couples availing themselves of such technology is also increasing. While initial evaluations of the children conceived through such methodologies are reassuring, small numbers and short duration of follow up limit these studies. Unanswered questions regarding the overall safety of these procedures remain, particularly with regard to imprinted genes. Imprinted genes, those alleles expressed preferentially from only one parent, are key to early embryogenesis and the importance of the preimplantation period for the proper implementation of these imprinted genes is surfacing.
Several lines of evidence suggest further research into assisted reproduction and congenital anomalies is warranted. First, only now emerging are sufficiently large, well-designed and well- controlled studies of congenital anomalies in children conceived by IVF. The analysis of birth defects in any population is complicated by clear delineation of controls and cases, consistent determination of anomalies, and sufficient sample sizes. Recent analyses in two different, large, assisted reproduction populations suggest the rate of congenital malformations may be twice that noted for spontaneous conceptions. Delineation of specific malformations remains confounded by small sizes.
Second, concern is reported regarding the increased presence of genetic disorders known to result from imprinting among children conceived by IVF. Beckwith Wiedemann syndrome (BWS), a disorder associated with overgrowth and malformations due to a specific imprinting abnormality on chromosome 11, may occur more frequently among children conceived by IVF. Also of interest is a striking increase in BWS among monozygotic twin gestations, lending additional evidence to the proposal that perturbations occurring during preimplantation may affect sensitive methylation states.
Lastly, evidence from assisted reproduction in cattle and sheep points to a similar condition in animals referred to as Large Offspring Syndrome. Recognized as a clinical entity for the past several years, recent analyses of imprinted genes and media alterations has shed new light on the influence of imprinted genes in this disorder. Examination of each of these three areas will help direct further investigations into the role of assisted reproduction and congenital malformations.