Silver-Russell syndrome: genetic basis and molecular genetic testing

Thomas Eggermann,Matthias Begemann,Gerhard Binder,Sabrina Spengler

doi:10.1186/1750-1172-5-19

Abstract

Imprinted genes with a parent-of-origin specific expression are involved in various aspects of growth that are rooted in the prenatal period. Therefore it is predictable that many of the so far known congenital imprinting disorders (IDs) are clinically characterised by growth disturbances. A noteable imprinting disorder is Silver-Russell syndrome (SRS), a congenital disease characterised by intrauterine and postnatal growth retardation, relative macrocephaly, a typical triangular face, asymmetry and further less characteristic features. However, the clinical spectrum is broad and the clinical diagnosis often subjective. Genetic and epigenetic disturbances can meanwhile be detected in approximately 50% of patients with typical SRS features. Nearly one tenth of patients carry a maternal uniparental disomy of chromosome 7 (UPD(7)mat), more than 38% show a hypomethylation in the imprinting control region 1 in 11p15. More than 1% of patients show (sub)microscopic chromosomal aberrations. Interestingly, in ~7% of 11p15 hypomethylation carriers, demethylation of other imprinted loci can be detected. Clinically, these patients do not differ from those with isolated 11p15 hypomethylation whereas the UPD(7)mat patients generally show a milder phenotype. However, an unambiguous (epi)genotype-phenotype correlation can not be delineated.We therefore suggest a diagnostic algorithm focused on the 11p15 hypomethylation, UPD(7)mat and cryptic chromosomal imbalances for patients with typical SRS phenotype, but also with milder clinical signs only reminiscent for the disease.

Highlights

Imprinted genes with a parent-of-origin specific expression are involved in various aspects of growth that are rooted in the prenatal period
Imprinted genes with a parent-of-origin specific expression are involved in various aspects of growth and behaviour that are rooted in the prenatal period and many of the so far known congenital imprinting disorders (IDs) are clinically characterised by growth disturbances
Knockout of H19 removing the whole RNA coding sequence but leaving the promoter and surrounding transcription unit intact had no effect on the imprinted expression of IGF2 [40]. These results indicate that the RNA itself might be non-functional, the fact that H19 is a relatively highly conserved gene among mammals (77% identity between human and mouse) suggests a profound functional relevance

Summary

Introduction

Imprinted genes with a parent-of-origin specific expression are involved in various aspects of growth that are rooted in the prenatal period. The most probable explanation for the SRS phenotype in UPD(7)mat carriers is the disturbed expression of imprinted genes on chromosome 7. Neither point mutations in the coding region nor aberrant methylation of GRB10 have been detected in SRS patients despite extensive screening studies (for review: [22,23,24]).

Results

Conclusion