In vitro fertilization (IVF) has been linked to an increased risk for imprinting disorders in offspring. The data so far have predominantly been retrospective, comparing the rate of IVF conceptions in affected patients with controls. We describe a series of fetuses with omphalocele that were tested for Beckwith-Wiedemann syndrome (BWS) and subsequently ascertained as to whether pregnancies were conceived by assisted reproductive technologies (ART).
Fetuses were tested for BWS by Southern blot, PCR based methods, and methylation analysis to identify the imprinting status at primarily the IC2 locus, KCNQ1OT1, as well as IC1, H19/IGF-2. Some fetuses were also tested for uniparental disomy of chromosome 11p.
We tested 301 fetuses with omphalocele for BWS. Forty samples were positive. Sixteen were from IVF pregnancies, for an overall rate of 40%. Such as high proportion of IVF pregnancies in a series of BWS-positive fetuses has not been described previously. Possible factors such as twinning and ascertainment bias are discussed.
We found about a 20-fold overrepresentation of IVF cases in fetuses with BWS/omphalocele when compared with the rate of ART pregnancies in the USA (p < .0001). Our series provides support for an association of IVF and BWS. Patients should be counseled about these risks and made aware of the availability of prenatal diagnosis for detection.
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Cox GF, Burger J, Lip V, et al. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet. 2002;71:162–4.
Glenn CC, Porter KA, Jong MT, et al. Functional imprinting and epigenetic modification of the human SNRPN gene. Hum Mol Genet. 1993;2(12):2001–5.
Orstavik KH, Eiklid K, van der Hagen CB, Spetalen S, Kierulf K, Skjeldal O, et al. Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am J Hum Genet. 2003;72(1):218–21.
DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alteration of LIT1 and H19. Am J Hum Genet. 2003;72:156–60.
Shuman S, Beckwith JB, Smith AC et al. Beckwith-Wiedemann syndrome, in Gene Reviews, Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle: University of Washington; 1993–2015.
Maher ER, Brueton LA, Bowdin SC, Luharia A, Cooper W, Cole TR, et al. Beckwith-Wiedemann syndrome and assisted reproductive technology (ART). J Med Genet. 2003;40:62–4.
Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Weidemann syndrome related to the abnormal imprinting of the KCNQ1OT gene. Am J Hum Genet. 2003;72:1338–41.
Halliday J, Oke K, Breheny S, Algar E, Amor DJ. Beckwith-Wiedemann syndrome and IVF: a case control study. Am J Hum Genet. 2005;75:526–8.
Chang AS, Moley KH, Wangler M, Feinberg AP, DeBaun MR. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology: a case series of 19 patients. Fertil Steril. 2005;83:349–54.
Sutcliffe AG, Peters CJ, Bowdin S, Temple K, Reardon W, Wilson L, et al. Assisted reproductive therapies and imprinting disorders—a preliminary British survey. Hum Reprod. 2006;21:1009–11.
Lidegaard O, Pinborg A, Andersen AN. Imprinting diseases and IVF: Danish National IVF cohort study. Hum Reprod. 2005;20:950–4.
Doornbos ME, Maas SM, McDonnell J, Vermeiden JP, Hennekam RC. Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study. Hum Reprod. 2007;22(9):2476–80.
Bowdin S, Allen C, Kirby G, Brueton L, Afnan M, Barratt C, et al. A survey of assisted reproductive technology births and imprinting disorders. Hum Reprod. 2007;22(12):3237–40.
Kallen, Finnström O, Lindam A, Nilsson E, Nygren KG, Otterblad Olausson P. Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: data for 25 years. Hum Reprod. 2010;4:1026–34.
Whittington JE, Butler JV, Holland AJ. Short report: changing rates of genetic subtypes of Prader–Willi syndrome in the UK. Eur J Hum Genet. 2007;15:127–30.
Bittel DC, Butler MG. Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med. 2005;7(14):1–20.
Mussa A, Molinatto C, Cerrato F, Palumbo O, Carella M, Baldassarre G, et al. Assisted reproductive techniques and risk of Beckwith-Wiedemann syndrome. Pediatrics. 2017;140(1):e20164311.
Wilkins-Haug L, Porter A, Hawley P, Benson CB. Isolated fetal omphalocele, Beckwith-Wiedemann syndrome, and assisted reproductive technologies. Birth Defects Res A Clin Mol Teratol. 2009;85(1):58–62.
Elliott M, Bayly R, Cole T, Temple IK, Maher ER, Elliott M. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet. 1994;46(2):168–74.
www.cdc.gov/art accessed 4/21/2018.
Lee MP, DeBaun MR, Mitsuya K, et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc Natl Acad Sci U S A. 1999;96(9):5203–8.
Mitsuya K, Meguro M, Lee MP, Katoh M, Schulz TC, Kugoh H, Yoshida MA, Niikawa N, Feinberg AP, Oshimura M LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids. Hum Mol Genet 1999;8(7):1209–17.16, 1217.
Smilinich NJ, Day C, Fitzpatrick GV, et al. A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc Natl Acad Sci U S A. 1999;96:8064–9.
Coffee B, Muralidharan K, Highsmith WE Jr, et al. Molecular diagnosis of Beckwith-Wiedemann syndrome using quantitative methylation-sensitive polymerase chain reaction. Genet Med. 2006;8(10):628–34.
Johnson JP, Waterson J, Schwanke C, Schoof J. Genome-wide androgenetic mosaicism. Clin Genet. 2014;85:282–5.
Bliek J, Maas SM, Ruijter JM, Hennekam RC, Alders M, Westerveld A, et al. Increased tumour risk for BWS patients correlates with H19 and KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in in familial cases of BWS. Hum Mol Genet. 2001;10:467–76.
Zeschnigk M, Albrecht B, Buiting K, Kanber D, Eggermann T, Binder G, et al. IGF2/H19 hypomethylation in Silver-Russell syndrome and isolated hemihypoplasia. Eur J Hum Genet. 2008;16(3):328–34.
www.medcalc.org/calc/comparison_of_proportions.php. Accessed 9/15/2017.
Grati FR, Turolla L, D’Ajello P, Ruggeri M, Miozzo M, Bracalente G, et al. Chromosome 11 segmental paternal isodisomy in amniocytes from two fetuses with omphalocele: new highlights on phenotype-genotype correlations in Beckwith-Wiedemann syndrome. J Med Genet. 2007;44:257–63.
Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Drake P. Births: final data for 2016. National Vital Statistics Reports; vol 67 no 1. Hyattsville, MD: National Center for Health Statistics. 2018.
http://www.sample-size.net/confidence-interval-proportion/. Accessed 9/15/2017.
Elalaoui SC, Garin I, Sefiani A, Perez de Nanclares G. Maternal hypomethylation of KvDMR in a monozygotic male twin pair discordant for Beckwith-Wiedemann syndrome. Molecular Syndromology. 2014;5(1):41–6.
Bestor TH. Imprinting errors and developmental asymmetry. Philos Trans R Soc Lond Ser B Biol Sci. 2003;358:1411–5.
Weksberg R, Shuman C, Caluseriu O, Smith AC, Fei YL, Nishikawa J, et al. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet. 2002;11:1317–25.
Bliek J, Alders M, Maas SM, Oostra RJ, Mackay DM, van der Lip K, et al. Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. Eur J Hum Genet. 2009;17(12):1625–34.
Manipalviratn S, De Cherney A, Segars J. Imprinting disorders and assisted reproductive technology. Reprod Med Biol. 2014;13:193–202.
Hiura H, Okae H, Chiba H, Miyauchi N, Sato F, Sato A, et al. Imprinting and methylation errors in ART. Reprod Med Biol. 2014;13:193–202.
Kafri T, Ariel M, Brandeis M, Shemer R, Urven L, McCarrey J, et al. Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line. Genes Dev. 1992;6:705–14.
Mackay DJ, Boonen SE, Clayton-Smith J, Goodship J, Hahnemann JM, Kant SG, et al. A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet. 2006 Sep;120(2):262–9.
Sakian S, Louie K, Wong EC, Havelock J, Kashyap S, Rowe T, et al. Altered gene expression of H19 and IGF2 in placentas from ART pregnancies. Placenta. 2015;36:1100–5.
Marchesi DE, Qiao J, Feng HL. Embryo manipulation and imprinting. Semin Reprod Med. 2012;30:323–34.
The work reported here is the result of routine provision of medical attention at the standard of care, with data collected solely for patient care purposes. No additional data were collected or medical intervention undertaken for the purposes of this study. As such, a Research Involving Human Subjects Committee was not convened.
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Johnson, J.P., Beischel, L., Schwanke, C. et al. Overrepresentation of pregnancies conceived by artificial reproductive technology in prenatally identified fetuses with Beckwith-Wiedemann syndrome. J Assist Reprod Genet 35, 985–992 (2018). https://doi.org/10.1007/s10815-018-1228-z
- Beckwith-Wiedemann syndrome