Submicroscopic genomic alterations in Silver-Russell syndrome and Silver-Russell-like patients.

Background: Silver-Russell syndrome (SRS, OMIM 180860) features fetal and postnatal growth restriction and variable dysmorphisms. Genetic and epigenetic aberrations on chromosomes 7 and 11 are commonly found in SRS. However, a large fraction of SRS cases remain with unknown genetic aetiology.

Methods: 22 patients with a diagnosis of SRS (10 with H19 hypomethylation and 12 of unknown molecular aetiology) and their parents were studied with the Affymetrix 250K Sty microarray. Several analytical approaches were used to identify genomic aberrations such as copy number changes (CNCs), loss of heterozygosity (LOH) and uniparental disomy (UPD). Selected CNCs were verified with quantitative real-time PCR.

Results: The largest unambiguous CNCs were found in patients with previously molecularly unexplained SRS with relatively mild phenotypes: a heterozygous deletion of chromosome 15q26.3 including the IGF1R gene (2.6 Mb), an atypical distal 22q11.2 deletion (1.1 Mb), and a pseudoautosomal region duplication (2.7 Mb) in a male patient. LOH regions of potential relevance to the SRS phenotype were also identified. Importantly, no duplications or UPD of chromosomes 7 or 11 were identified.

Conclusion: Unexpected submicroscopic genomic events with pathogenic potential were found in three patients with molecularly unexplained SRS that was mild. The findings emphasise that SRS is heterogeneous in genetic aetiology beyond the major groups of H19 hypomethylation and maternal UPD7 and that unbiased genome-scale screens may reveal novel genotype-phenotype correlations.