Hypomethylation of the H19 Gene Causes Not Only Silver-Russell Syndrome (SRS) but Also Isolated Asymmetry or an SRS-Like Phenotype

Abstract

The H19 differentially methylated region (DMR) controls the allele-specific expression of both the imprinted H19 tumor-suppressor gene and the IGF2 growth factor. Hypermethylation of this DMR--and subsequently of the H19 promoter region--is a major cause of the clinical features of gigantism and/or asymmetry seen in Beckwith-Wiedemann syndrome or in isolated hemihypertrophy. Here, we report a series of patients with hypomethylation of the H19 locus. Their main clinical features of asymmetry and growth retardation are the opposite of those seen in patients with hypermethylation of this region. In addition, we show that complete hypomethylation of the H19 promoter is found in two of three patients with the full clinical spectrum of Silver-Russell syndrome. This syndrome is also characterized by growth retardation and asymmetry, among other clinical features. We conclude that patients with these clinical features should be analyzed for H19 hypomethylation.

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

“…In fact, in most of the SRS patients, loss of DNA methylation at the H19 ICR was not detected in all of the blood cells analysed, and also tissue-derived fibroblasts showed mosaic loss of methylation. (1,3) This suggests that the loss of H19 methylation in these sporadic cases did not originate from the sperm, in which case it would have persisted in all the cells of the conceptus. Rather, the loss of methylation likely reflects an early embryonic event.…”

“…1B). Importantly, the loss of methylation in about a third of patients correlated with strongly reduced IGF2 expression and biallelic expression of H19 (1)(2)(3)20) Remarkably, in about 10% of Beckwith-Wiedemann Syndrome patients, there is the exact opposite epigenetic alteration. These patients have biallelic DNA methylation at the H19 ICR and H19 promoter, with loss of H19 expression, and biallelic expression of IGF2 (Fig.…”

“…Proper establishment, and especially the subsequent somatic maintenance of these marks, is crucial, since their deregulation may lead to complex diseases in humans, and is frequently also observed in cancer. (18,19) Remarkably, three independent studies on Silver-Russell Syndrome (1)(2)(3) now report loss of DNA methylation at the H19 ICR, in about a third of patients. Silver-Russell Syndrome (SRS; OMIM 180860) is a congenital disorder characterised by intrauterine and postnatal growth retardation, facial dysmorphism and a series of minor features, including relative macrocephaly, skeletal asymmetry, early or precocious puberty, and genital abnormalities.…”

“…Overexpression of IGF2, due to different reasons, is one of the causes of the Beckwith-Wiedemann overgrowth syndrome (BWS) in humans. Now, three exciting studies pinpoint the imprinted IGF2 gene as being also involved in the Silver-Russell Syndrome (SRS) (1)(2)(3) a human syndrome that could be considered the opposite of BWS, since intrauterine and postnatal growth retardation are its main symptoms.…”

“…The novel studies now indicate that epigenetic modifications at the IGF2-H19 domain are causally involved in Silver-Russell Syndrome. (1)(2)(3) This raises interesting questions about possible other epigenetic mechanisms.…”