Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

Abstract

International audienceThis study was an investigation of 79 patients referred to the Wessex Regional Genetics Laboratory with suspected Russell-Silver Syndrome or unexplained short stature/intra uterine growth restriction, warranting genetic investigation. Methylation status was analysed at target sequences within eleven imprinted loci (PLAGL1, IGF2R, PEG10, MEST1, GRB10, KCNQ1OT1, H19, IGF2P0, DLK1, PEG3, NESPAS). 37% (29/79) of samples were demonstrated to have a methylation abnormality. The commonest finding was a loss of methylation at H19 (23/29), as previously reported in Russell-Silver Syndrome. In addition, four of these patients had methylation anomalies at other loci, of whom two show hypomethylation of multiple imprinted loci, and two showed a complete gain of methylation at IGF2R. This latter finding was also present in five further patients who did not have demonstrable changes at H19. In total, 7/79 patients showed a gain of methylation at IGF2R and this was significantly different from a normal control population of 267 individuals (p=0.002). This study demonstrates the importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus in growth restriction

Frequency and characterization of DNA methylation defects in children born SGA

“…However, in line with recent publications, we detected IGF2R DNA methylation in children born SGA S Bens et al DMR2 hypermethylation repeatedly and in similar frequency (2 and 5/50 samples, depending on the strategy of analyzing pyrosequencing data) within our control cohort. 12,41 The lack of phenotypic correlation in our and previous studies leads to the assumption that IGF2R DMR2 hypermethylation most likely represents an epigenetic polymorphism, a Mendelian inheritance cannot be excluded from our observations. We conclude that aberrant methylation at imprinted loci in children born SGA exists, but seems to be rare if known imprinting syndromes are excluded.…”

“…12 Turner et al 12 detected significant enrichment of IGF2R hypermethylation in 7/79 patients with growth restrictions versus 3/267 controls. In this study, we detected IGF2R hypermethylation in 5/98 children born SGA.…”

“…6 Results have been very heterogeneous with most studies analyzing chorionic villi or placenta tissue. [12][13][14][15] Nevertheless, placental tissue displays an intermediate distribution of methylation as compared, for example, with embryonal epithelial cells. 16,17 Moreover, there is greater epigenetic variation in extraembryonic than in embryonic tissue.…”

“…They hypothesized that hypermethylation of IGF2R DMR2 results in increased expression of IGF2R and lower circulating levels of IGF2, eventually explaining growth restriction. 12 In order to gain more insight in the underlying causes of growth restriction, we here performed a screening study of 10 imprinted loci, including those associated with fetal growth restriction, on peripheral blood of a large cohort of 98 children born SGA.…”

No evidence for pathogenic variants or maternal effect of ZFP57 as the cause of Beckwith–Wiedemann Syndrome

“…1,2 Recently, mechanisms influencing imprinting disorders in trans have been identified. Hypomethylation of multiple imprinted loci (HIL) is described in different imprinting syndromes including transient neonatal diabetes mellitus type 1 (TNDM1; MIM 601410), 4 BWS, [5][6][7] Silver-Russell syndrome (SRS; MIM 180860)/growth restriction, 8,9 and in a single patient with the clinical phenotype of BWS and Prader-Willi syndrome. 10 Recessive ZFP57 mutations were identified in more than half of the TNDM1 cases displaying HIL.…”