Multiple segmental uniparental disomy associated with abnormal DNA methylation of imprinted Loci in silver-russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS; online inheritance in man 180860) is a low-birth-weight syndrome characterized by postnatal growth restriction and variable dysmorphic features. Although maternal uniparental disomy (UPD) of chromosome 7 and hypomethylation of H19 have been reported in up to 50% of all cases, no unifying mechanism is apparent. SUBJECTS AND METHODS: Ten patients and their parents were studied using the Illumina GoldenGate methylation array and the Illumina 370K HumHap single-nucleotide polymorphism array to identify aberrations in DNA methylation as well as genomic changes including copy number changes and uniparental disomy events. RESULTS: We found evidence of UPD events outside chromosome 7 in all patients. In up to 30% of patients with SRS, DNA methylation changes occur in imprinted gene loci outside 11p15.5 (PEG3, PLAGL1, and GRB10), not previously consistently linked with SRS. Furthermore, hypermethylation of GRB10 was associated with increased mRNA expression. In addition, 20% of patients appear to have DNA methylation abnormalities within multiple loci. Not all the imprinted loci with methylation defects were affected directly by UPD. CONCLUSIONS: The association of widespread UPD associated with abnormal methylation and mRNA expression in imprinted genes in SRS is consistent with the concept of UPD as an initial genomic abnormality leading to unstable DNA methylation within the regulatory network of imprinted genes. Furthermore, disruption of any one of these genes may contribute to the heterogeneous clinical spectrum of SRS.

Network of European studies of genes in growth (NESTEGG).

The network of European studies of genes in growth (NESTEGG) is an international growth genomics project, focusing on the birth size phenotypes of small for gestational age (SGA) and idiopathic short stature. Seven hundred controls and 1,275 cases with their parents have been recruited. Detailed clinical histories and auxological measurements are recorded in a clinical database. Candidate gene studies are being undertaken with the study DNA samples. These genetic data will be used to explore associations with the clinical phenotypes of short stature and SGA birth size, and, in a subset, response to growth hormone (GH) therapy. This article describes the study methodology and reviews the association of the exon 3-deleted genotype of the GH receptor with GH responsiveness in GH-treated children born SGA.

Contrasting clinical manifestations of SDHB and VHL associated chromaffin tumours.

Mutations in succinate dehydrogense-B (SDHB) and the von Hippel-Lindau (VHL) genes result in an increased risk of developing chromaffin tumours via a common aetiological pathway. The aim of the present retrospective study was to compare the clinical phenotypes of disease in subjects developing chromaffin tumours as a result of SDHB mutations or VHL disease. Thirty-one subjects with chromaffin tumours were assessed; 16 subjects had SDHB gene mutations and 15 subjects had a diagnosis of VHL. VHL-related tumours were predominantly adrenal phaeochromocytomas (22/26; 84.6%), while SDHB-related tumours were predominantly extra-adrenal paragangliomas (19/25; 76%). Median age at onset of the first chromaffin tumour was similar in the two cohorts. Tumour size was significantly larger in the SDHB cohort in comparison with the VHL cohort (P=0.002). Multifocal disease was present in 9/15 (60%) of the VHL cohort (bilateral phaeochromocytomas) and only 3/16 (19%) of the SDHB cohort, while metastatic disease was found in 5/16 (31%) of the SDHB cohort but not in the VHL cohort to date. The frequency of symptoms, hypertension and the magnitude of catecholamine secretion appeared to be greater in the SDHB cohort. Renal cell carcinomas were a feature in 5/15 (33%) of the VHL cohort and 1/16 (6%) of the SDHB cohort. These data indicate that SDHB-related tumours are predominantly extra-adrenal in location and associated with higher catecholamine secretion and more malignant disease, in subjects who appear more symptomatic. VHL-related tumours tend to be adrenal phaeochromocytomas, frequently bilateral and associated with a milder phenotype.

Association between insulin-like growth factor I (IGF-I) polymorphisms, circulating IGF-I, and pre- and postnatal growth in two European small for gestational age populations.

The purpose of this study was to assess the association of IGF-I and birth size by studying small for gestational age (SGA) subphenotypes and undertaking more detailed analysis of IGF-I genetic markers. SGA subjects from Haguenau, France (n = 113), and Gothenburg, Sweden (n = 174), were studied. The Swedish subjects were subphenotyped according to postnatal growth (114 short SGA and 60 SGA catch-up). IGF-I dinucleotide repeat and single nucleotide polymorphism (SNP) markers were studied, and haplotypes were generated in the Swedish short SGA group by identity of state. Association analysis was undertaken using the Monte Carlo method of association analysis of multiallelic markers for dinucleotide repeat markers, by exact chi(2) analysis for SNPs and by ANOVA for serum IGF-I levels. IGF-I genotype was associated with the SGA phenotype, in particular with symmetrical SGA and low birth weight, and with IGF-I levels in SGA subjects. Association with postnatal growth was different in the two populations, which may reflect the power of the smaller subphenotype groups. Haplotype analysis in the Swedish short SGA subjects showed that the region of association lay between the promoter and intron 2 of the IGF-I gene. These studies validate the association of the IGF-I gene with birth size and refine the region of association in Swedish short SGA subjects.