Segmental maternal UPD(7q) in Silver–Russell syndrome

To the Editor: Silver–Russell syndrome (SRS, RSS, OMIM 180860) is a clinically and genetically heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation, typical craniofacial signs including a relative macrocephaly, asymmetry of body and limbs, clinodactyly V and further less common features. Two major (epi)genetic disturbances are associated with SRS: in more than 38% of patients, a hypomethylation of the imprinted H19/IGF2 locus in 11p15 can be observed (1). Seven to 10% of patients carry a maternal uniparental disomy of chromosome 7 (UPD(7)mat). Clinically, the 11p15 hypomethylation carriers show the characteristic SRS phenotype, while clinical features of UPD(7)mat patients are less characteristic (2). In addition to the 11p15 epimutation and UPD(7)mat, several patients with SRS features carry chromosomal aberrations [for review, see (3, 4)].However, these reports have to be considered with caution because intrauterine and postnatal growth retardation is a non-specific finding, and some of these patients show additional clinical signs not consistent with SRS. Nevertheless, the description of four patients with 7p aberrations and a SRS phenotype (3) led to extensive analyses of candidate genes in the proximal 7p region and among them the imprinted gene GRB10. However, despite numerous studies focusing on the search for point mutations in 7p-encoded genes, no pathogenic mutations have been identified so far that might be functionally related to the SRS phenotype. Surprisingly, there is evidence that chromosomal regions in 7q are also involved in SRS aetiology. The first hint was reported by Hannula et al. (5) who described a SRS case with a segmental UPD(7)mat restricted to the distal band of 7q. A further patient with a mosaic segmental maternal uniparental isodisomy for chromosome 7q was recently published by Reboul et al. (6): apart from cystic fibrosis, this patient showed a severe intrauterine and postnatal growth restriction but no further clinical signs reminiscent of SRS. Both cases emphasize the importance of human imprinted genes in 7q for human growth. In 7q31qter, three imprinted genes (carboxypeptidase A4/CPA4, mesoderm-specific transcript/ paternally expressed gene 1/MEST/PEG1, and coatomer protein complex subunit g2/COPG2) and two imprinted non-coding RNAs (MEST intronic transcript 1/MESTIT1 and COPG2 intronic transcript 1/CIT1/COPG2IT1) are localized. However, screening studies on mutations in these genes and transcripts failed to detect any pathogenic variants (7–11). In our routine diagnostic screening for UPD(7)mat, we have now identified two patients with SRS features carrying a segmental UPD restricted to 7q which affects the abovementioned imprinted transcripts (Table 1). In both patients, 11p15 hypomethylation and cytogenetic aberrations had been excluded before. Genomic DNA was isolated by a simple salting-out procedure, and bisulfite modification was performed using the EZ DNA MethylationGold Kit (Zymo Research, Freiburg, Germany). For UPD7 detection, we then carried out a modified multiplex methylation-specific PCR (MSPCR) assay published by Moore et al. (12), which determines the methylation status of the PEG1/ MEST promoter region in 7q32. After detection of UPD(7)mat by MS-PCR, we characterized the extent of the segmental matUPD7q by microsatellite analyses. As shown in Table 1, the UPD(7)mat segment in our cases included .100 Mb from 7q11.2 to 7qter. Clinically, both patients showed signs reminiscent of SRS (Table 2). Case 1 (SR85): Intrauterine growth retardation was absent; the German girl was born 3 weeks before term with a birth weight of 2800 g (20.45 SD score) and a length of 46 cm (21.16 SD score). Postnatal growth was restricted, and the girl presented with short stature at the age of 5.3 years (height 99.5 cm, 22.86 height SD score). In addition, relative macrocephaly, frontal bossing and low-set ears were reported and no