(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.