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Beckwith-Wiedmann syndrome in cattle is called large offspring syndrome (LOS). Both syndromes can result in the overgrowth of the fetus and enlarged babies. These disorders can be associated with in vitro fertilization. Knowing which genes cause them will allow doctors to choose embryos for implantation that do not have the molecular markers for BWS.

Genetics behind fetal overgrowth syndrome found

New research could lead to safer, more efficient assisted reproduction procedures.

Humans and cattle share a similar epigenetic fetal overgrowth disorder that occurs more commonly following assisted reproduction procedures. In humans, this disorder is called Beckwith-Wiedemann syndrome (BWS), and in cattle it is called large offspring syndrome (LOS). Both syndromes can result in the overgrowth of the fetus and enlarged babies. This naturally occurring, but rare syndrome can cause physical abnormalities in humans and cattle. In cattle, it often results in the deaths of newborn calves and birth injuries to their mothers.

The study was published in the Proceedings of the National Academy of Sciences (PNAS).

Research at the University of Missouri has identified a number of genes that contribute to LOS in cattle. Rocío Melissa Rivera, associate professor in the Universiy of Missouri (MU) College of Agriculture, Food and Natural Resources, says identifying these genes in cattle will help identify BWS genes in humans.

"The human disorder BWS is physically and molecularly very similar to LOS in cattle," says Rivera. "By identifying the LOS genes, we can take steps toward discovering which genes cause BWS in humans. Because these disorders have been associated with pregnancies from in vitro fertilization, knowing which genes cause these disorders will allow doctors to choose embryos for implantation that do not have the molecular markers for BWS."

Beckwith-Wiedmann syndrome results in babies that grow and gain weight more rapidly than normal in the womb and throughout early childhood. Many children with BWS have enlarged tongues, defects in their abdominal wall, asymmetric growth as some body parts grow faster than others, and are at a higher risk for cancer throughout childhood. BWS, other than the most severe cases, is not fatal to humans unless they develop undetected cancer.

Large offspring syndrome in cattle has many similar characteristics to BWS in humans, including rapid growth, weight gain in the womb, large tongues and abdominal wall defects. Calves with LOS can die within a week of birth because many cannot support their own weight and size.

"The use of in vitro fertilization is common in cattle breeding, so LOS is a potential problem those breeders face. It is important for breeders to be able to identify the genetic causes of LOS to avoid impregnating their cattle with embryos that are predisposed to the disorder. This will allow the breeding process to be much more efficient as well as safe for the cattle being bred."

Rocío Melissa Rivera PhD, associate professor, Universiy of Missouri College of Agriculture, Food and Natural Resources

Significance
Large offspring syndrome (LOS) is a fetal overgrowth condition that mimics the human syndrome Beckwith–Wiedemann. These conditions have been observed with higher incidence in offspring conceived with the use of assisted reproductive technologies and are believed to be the result of misregulation of a set of genes that are expressed only from the maternally or paternally inherited chromosomes. These genes are known as imprinted genes. In our study, we demonstrate that the kidney, brain, muscle, and liver of LOS fetuses show misregulation of multiple imprinted genes when compared with controls. Furthermore, we show that the magnitude of overgrowth in LOS fetuses correlates with the number of misregulated imprinted genes. Our results may help create diagnostics for these fetal syndromes.

Abstract
Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith–Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day ∼105 Bos taurus indicus × Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS.

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