Multi-locus imprinting disturbances of Beckwith-Wiedemann and Large offspring syndrome/Abnormal offspring syndrome: A brief review.

In vitro fertilization and somatic cell nuclear transfer are assisted reproduction technologies commonly used in humans and cattle, respectively. Despite advances in these technologies, molecular failures can occur, increasing the chance of the onset of imprinting disorders in the offspring. Large offspring syndrome/abnormal offspring syndrome (LOS/AOS) has been described in cattle and has features such as hypergrowth, malformation of organs, and skeletal and placental defects. In humans, Beckwith-Wiedemann syndrome (BWS) has phenotypic characteristics similar to those found in LOS/AOS. In both syndromes, disruption of genomic imprinting associated with loss of parental-specific expression and parental-specific epigenetic marks is involved in the molecular etiology. Changes in the imprinting pattern of these genes lead to loss of imprinting (LOI) due to gain or loss of methylation, inducing the emergence of these syndromes. Several studies have reported locus-specific alterations in these syndromes, such as hypomethylation in imprinting control region 2 (KvDMR1) in BWS and LOS/AOS. These LOI events can occur at multiple imprinted loci in the same affected individual, which are called multi-locus methylation defect (MLMD) events. Although the bovine species has been proposed as a developmental model for human imprinting disorders, there is little information on bovine imprinted genes in the literature, even the correlation of epimutation data with clinical characteristics. In this study, we performed a systematic review of all the multi-locus LOI events described in human BWS and LOS/AOS, in order to determine in which imprinted genes the largest changes in the pattern of DNA methylation and expression occur, helping to fill gaps for a better understanding of the etiology of both syndromes.