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Epigenetics in Silver-Russell syndrome

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Silver-Russell syndrome (SRS) is a clinically heterogeneous syndrome characterized by intra-uterine and postnatal growth retardation with spared cranial growth, dysmorphic features and frequent body asymmetry. Various cytogenetic abnormalities have been described in a small number of SRS or SRS-like cases involving chromosomes 7, 8, 11, 15, 17 and 18. However, until recent data became available involving imprinted genes on chromosome 7 and chromosome 11p15, the molecular cause of the syndrome was unknown in most cases. Genomic imprinting is the best example of transcriptional control of genes by epigenetic modifications. Many imprinted genes play key roles in fetal and placental growth and behaviour. This is illustrated in SRS, which can now be considered as a new imprinting disease model. These new findings in the pathophysiology of SRS allow long-term follow-up studies to be performed based on molecular diagnosis. This could help to define appropriate clinical guidelines regarding growth and feeding difficulties.

Section snippets

Epigenetics and gene expression

Epigenetics refers to chromatin modifications, which do not affect the DNA sequence itself, resulting in the regulation of gene expression. These modifications are stably heritable through mitosis and sometimes through meiosis.*7, 8 Epigenetic changes are crucial for development (allowing the differentiation of different cell types), as well as for X-chromosome inactivation and genomic imprinting. Epigenetic changes also occur in pathological processes involved in cancer and other diseases.9

Dysregulation of imprinted genes expression in SRS

Various cytogenetic abnormalities involving chromosomes 7, 8, 11, 15, 17 and 18 have been described in a small number of SRS or SRS-like cases.32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Although mainly sporadic, familial SRS cases have been reported with different modes of inheritance.44 It has recently been found that UPD of chromosome 7 and, particularly, dysregulation of imprinted genes on chromosomal region 11p15 result in molecular confirmation of the diagnosis in approximately 70% of

Summary

SRS has long been considered as a heterogeneous syndrome both clinically and genetically, probably due to the absence of a consensus definition. The detection of mUPD7 in approximately 10% of cases and an epigenetic defect at 11p15 in 60% of cases will help to refine the diagnosis. As a result of this recent insight into SRS molecular pathogenesis, longitudinal follow-up studies of SRS patients based on their molecular defect (11p15 ICR1 epimutation or mUPD7) will be possible. It will allow

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