ESPE Abstracts

Background: Genomic imprinting is the process by which preferential methylation of one parental allele results in parent of origin specific expression of particular genes. Methylation is established during gametogenesis and is maintained throughout development. Alterations in any of the processes in the establishment and maintenance of methylation can lead to aberrant imprinting, which can result in either reactivation of the original silent allele or the silencing of the previously active allele. Many syndromes resulting from abnormal imprinting are recognized, most of them associated with abnormal growth patterns. In these individuals there may be abnormal methylation in one genetic locus or across multiple loci resulting in Multi Locus Imprinting Disturbance (MLID). Over the past few decades understanding of the genetic processes involved in the establishment and maintenance of methylation has increased. Mutations in ZFP57 gene are the most well recognized familial cause of MLID. In recent years a subcortical maternal protein complex (SMPC) within the oocyte, essential for early embryonic development, has been described, first in rats and subsequently in humans. Mutations in genes encoding these proteins have been reported in families with recurrent pregnancy loss and MLID.

Case Report: We present a case of a family with recurrent pregnancy loss and two siblings born with MLID. Sibling 1, born with severe IUGR and subsequent FTT, was diagnosed clinically with Silver Russell Syndrome. Methylation analysis at 11p15.5 revealed hypomethylation at the H19 and KCNQ1OT1 loci. Genome wide methylation analysis revealed hypomethylation at multiple loci throughout the genome. Sibling 2, also born with IUGR, developed hyperglycemia requiring insulin treatment during the first weeks of life, which subsequently resolved, compatible with a diagnosis of Transient Neonatal Diabetes Mellitus (TNDM). Methylation analysis revealed hypomethylation at 6q24.2 in the region of PLAGL1 in addition to abnormal methylation across multiple loci, with a different pattern to her brother. Sanger sequencing of ZFP57 in sibling 2 revealed no pathogenic variants. Analysis of maternal DNA including a panel of genes associated with recurrent pregnancy loss and MLID revealed a c.1069C>A homozygous variant in PADI6 (which encodes a SMPC protein component), resulting in substitution of Leucine for Isoleucine at position 357, close to where other variants associated with MLID have been described. This change has a frequency of 0.05% among Ashkenazi Jews with no homozygotes reported.

Conclusion: We believe this variant to be the cause of the recurrent pregnancy loss and MLID in the two siblings in this family.