A case of mosaic deletion of paternally‐inherited PLAGL1 and two cases of upd(6)mat add to evidence for PLAGL1 under‐expression as a cause of growth restriction

Abstract

PLAGL1 is one of a group of imprinted genes, whose altered expression causes imprinting disorders impacting growth, development, metabolism, and behavior. PLAGL1 over‐expression causes transient neonatal diabetes mellitus (TNDM type 1) and, based on murine models, under‐expression would be expected to cause growth restriction. However, only some reported individuals with upd(6)mat have growth restriction, giving rise to uncertainty about the role of PLAGL1 in human growth. Here we report three individuals investigated for growth restriction, two with upd(6)mat and one with a mosaic deletion of the paternally‐inherited allele of PLAGL1. These cases add to evidence of its involvement in pre‐ and early post‐natal human growth.

Maternal adverse childhood experiences (ACEs) and offspring imprinted gene DMR methylation at birth

“…That is, these pregnancy-specific stressors (e.g., financial distress) can be mutually exclusive from exposure to ACEs, exacerbating the association between ACEs and variable DNA methylation in infants. We specifically selected the imprinted genes PEG10/SGCE [ 29 , 30 ], NNAT , [ 31 , 32 ] IGF2 , [ 33 , 34 ] H19 [ 35 ], PLAGL1/HYMA1 , [ 36 ] PEG3 , [ 37 ] DLK1/MEG3, and MEG3-IG [ 38 , 39 ] for several reasons: 1) Perturbations in DNA methylation at these loci, particularly before germ layer specification, are stably transmitted during DNA replication to all subsequent lineages in the body throughout the life course [ 33 ]; 2) Imprinted genes are critically important to proper development and growth, and are known to be environmentally vulnerable to shifts in methylation [ 33 ]. Their importance is demonstrated by the fact that major abnormalities in imprinting are incompatible with life, while moderate abnormalities in imprinting are associated with a number of disorders and diseases, including cancer [ 34 ]; 3) DNA methylation profiles of imprinted genes are well documented; they are largely invariant across tissues, making it easier to identify deviations [ 38 ]; and 4) The DMRs of the above-mentioned genes chosen include four paternally methylated and four maternally methylated DMRs that contribute to establishment and/or maintenance of the imprinting status of 10 imprinted genes [ 29–39 ].…”