ART entails tenfold increased risk of Beckwith-Wiedemann syndrome
Assisted reproductive technology (ART) appears to carry a tenfold increase in the risk of Beckwith-Wiedemann syndrome (BWS) in children, with ART implicated in both the pathogenesis of genomic events and methylation anomalies, according to a study from Italy.
In a total of 379,872 live births delivered between 2005 and 2014, the prevalence of BWS was significantly higher in the births conceived with ART than in births conceived naturally (7 of 7,884 [1:1,126] vs 31 of 371,957 [1:12,254]; p<0.001). The absolute BWS risk per 1,000,000 live births was 887.9 in the ART group vs 83.3 in the natural group, yielding a relative risk of 10.7 (95 percent CI, 4.7 to 24.2). [Pediatrics 2017;doi:10.1542/peds.2016-4311]
In general, “[a]n increased risk of congenital defects is observed in ART children,” the authors said. “ART can disturb embryo development, leading to aberrant expression of imprinted genes.”
BWS, the most common imprinting disorder, is an overgrowth-cancer predisposition syndrome. Its clinical presentation is highly variable, including neonatal macrosomia, macroglossia, hyperinsulinemic hypoglycaemia, abdominal wall defects, ear anomalies, facial nevus flammeus, nephroureteral malformations, organomegaly and hemihyperplasia. [Eur J Pediatr 2011;170:1407–1411; Pediatr Nephrol 2012;27:397–406; Eur J Med Genet 2016;59:52–64]
“The molecular pathogenesis of BWS involves the altered gene expression by two imprinted clusters at the chromosome 11p15.5 region controlled by two imprinting centres responsible for differential expression on the basis of the parent of origin,” the authors noted.
Molecular testing of the 11p15.5 region in eight BWS newborns conceived with ART in a cohort of 663,834 newborns delivered between 1997 and 2014 (BWS prevalence, 1:9,908 live births) showed that four had imprinting centre 2 loss of methylation (IC2-LoM), two had paternal uniparental disomy (pUPD), and the remaining two had negative results.
“The molecular defects found in patients with BWS conceived through ART consist mostly of IC2-LoM, suggesting that either subfertility or ART procedures impair either the acquisition or the maintenance of the maternal methylation at the 11p15.5 region,” the authors explained. [Mol Hum Reprod 2009;15:471–477]
Furthermore, “[t]he finding of pUPD cases … demonstrated mosaic chromosome 11 pUPD, likely resulting from postfertilization somatic recombination. This is relevant because most research on ART-related imprinting disorders has focused on methylation disturbances of the oocyte or the male gamete. If confirmed, our findings of pUPD cases in ART-BWS cohorts would rather support a pathogenetic role of embryo manipulation,” they continued.
The authors also pointed out that given the increased occurrence of imprinting disorders in ART cohorts, the answer to the question of whether ART itself is the cause of the increased BWS prevalence has yet to be found.
“Rather than ART itself, it has been proposed that the genetic background of the infertile parents may be responsible for this phenomenon,” they said. [Hum Reprod 2007;22:2476–2480; 2012;27:2541–2548]
Further studies are warranted to investigate the effect of ART on human imprinting, as well as the long-term consequences of human embryonic manipulation that could play a role in the developmental origin of adult diseases.
“The association of IDs with ART should be mentioned in the informed consent proposed to couples considering ART-based reproductive choices: there is a clear increase in the relative risk of BWS, although the absolute risk for BWS is still small,” the authors said.
As a final point, they underscored the need for awareness in the scientific community and in the general population of ART-associated health risks. “[These risks] should be taken into account in the complex cultural debate on human procreation, a major issue in modern public health politics.”