(Epi)mutations in 11p15 significantly contribute to Silver–Russell syndrome: but are they generally involved in growth retardation?

Abstract

(Epi)mutations affecting chromosome 11p15 are meanwhile well known to be associated with growth disturbances. The finding of 11p15 mutations in the overgrowth disease Beckwith–Wiedemann syndrome (BWS) led to the identification of imprinted growth-promoting genes which are expressed paternally and of imprinted growth-suppressing genes in the same region that are expressed maternally. Recently, the opposite (epi)mutations of the same region have been reported to result in growth retardation: maternal duplications of 11p15 as well as hypomethylation of the telomeric 11p15 imprinting domain (ICR1) could be identified in patients with Silver–Russell syndrome (SRS), a disease which is in particular characterised by intrauterine and postnatal growth retardation. To elucidate whether 11p15 mutations are generally involved in growth retardation we screened 125 growth retarded patients, among them 47 patients with SRS-like features and 20 with isolated growth retardation. Additional 58 patients were presented with clinical signs not consistent with SRS. We excluded 11p15 duplications in all 123 families by short tandem repeat typing. ICR1 hypomethylation was investigated by Southern-blot analyses and was therefore restricted to samples with a large amount of DNA. We identified ICR1 hypomethylation in 20% of the patients with SRS-like features (n = 25). No further cases were detectable in the other two subgroups with isolated growth retardation (n = 20) and with clinical signs not consistent with SRS (n = 23), respectively. Our data show that 11p15 duplications are rare in growth retardation in general and that they seem to be restricted to patients with SRS features. Furthermore, testing for the ICR1 hypomethylation should also be focused on patients with SRS features. While the ICR1 epimutation is detectable with a significant frequency only in SRS patients, its role for isolated growth retardation remains to be elucidated.

Introduction

Intrauterine and postnatal growth retardation (IUGR/PGR) are typical hallmarks for different chromosomal disturbances, ranging from aneuploidies to cryptic chromosomal rearrangements and uniparental disomies (UPD). In UPDs of several chromosomes unbalanced expression of imprinted genes have been assumed to cause specific phenotypes (for review: [7]). A well known region carrying imprinted genes is 11p15: for this locus chromosomal rearrangements, paternal UPDs as well as epigenetic variations have been reported in Beckwith–Wiedemann syndrome (BWS) patients. This overgrowth syndrome is attributable to imprinted growth-promoting genes in 11p15 which are expressed paternally or to maternally expressed growth-suppressing genes in the same region (for review: [8]) (Fig. 1). Consequently it has been postulated that opposite genetic changes in the same region should result in growth retardation. Indeed, recent studies reveal an involvement of genetic variations in 11p15 in the aetiology of Silver–Russell syndrome (SRS) [1], [4] (Fig. 1). SRS is a clinically heterogenous syndrome which is mainly characterised by severe IUGR and PGR (<P3) (IUGR, PGR), a typical craniofacial gestalt, asymmetry and clinodactyly V. A clinical diagnostic scoring system to assist the diagnosis has not yet been established, thus the diagnosis is influenced by the experience of the clinical investigator. Furthermore, the clinical picture of adult SRS patients is less impressive compared to early infancy. Thus a laboratory diagnostic tool would be helpful to confirm the clinical diagnosis. The aetiology of the disease is also heterogeneous. The majority of cases are sporadic and chromosomal abnormalities have rarely been described, but in nearly 10% of cases maternal UPD of chromosome 7 can be detected (for review: [6]). Recently, in more than 30% of SRS patients an epimutation in the telomeric imprinting region in 11p15 could be demonstrated, further patients carried a maternal duplication of 11p15 [2], [4], [5]. These mutations are opposite to some of the 11p15 genetic variants detectable in BWS patients (Fig. 1). While all patients with 11p15 epimutations presented characteristic SRS features [5], the clinical picture in the carriers of maternal duplications seems to be milder (for review: [1]). It is therefore conceivable that (epi)mutations in 11p15 also contribute to other growth retardation phenotypes.

To further elucidate the significance of 11p15 duplications and epimutations for SRS aetiology and for growth retardation in general, we screened 125 growth retarded patients for mutations in 11p15 among them 47 probands with features reminiscent to SRS, 58 patients referred for exclusion of several types of UPD because of growth retardation, congenital anomalies, and further dysmorphic features, and 20 patients with isolated primordial growth retardation (Table 1).