Endocrine Abstracts

Background: Russell–Silver syndrome (RSS) is a heterogeneous condition characterised by pre- and post-natal growth retardation in association with variable dysmorphic features including triangular facies and body asymmetry. The condition has previously been linked to 2 genetic abnormalities: aberrant methylation at the 11p15.5 locus in 30–40% and maternal uniparental disomy (UPD) of chromosome 7 in 10% of cases. Up to 50% of children currently have no identified (epi)genetic cause for their clinical phenotype.

Aims: To investigate the possibility that there may be additional and possibly smaller regions of UPD elsewhere in the genome and if these regions are associated with changes in methylation of imprinted genes.

Methods: Using Illumina 370 HumHap SNP arrays a cohort of Caucasian children with RSS and their parents were studied. This cohort of patients were also studied for methylation across the whole genome using Illumina Goldengate Methylation chips.

Results: A number of regions with apparent inconsistencies in Mendelian inheritance not previously associated with RSS were identified on SNP genotyping. These regions were confirmed using highly informative short tandem repeat markers. These regions of UPD occur in two-thirds of patients studied with RSS (n=18). They do not occur in a control population of patients born small-for-gestational age (SGA) without features of RSS (n=10) or normal siblings (n=6). In addition, multiple regions were noted to have abnormal methylation patterns across the genome in 6 RSS patients compared to age and sex matched controls.

Discussion: In conclusion, a novel and extensive pattern of UPD has been identified in 70% of children with RSS. These include imprinted regions on chromosomes 6, 7, 11 and 14. These loci may further enhance our understanding of pathways involved in fetal and postnatal growth.