title: Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes.
abstract: BACKGROUND
  Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous condition characterised by severe intrauterine and postnatal growth retardation. Loss of DNA methylation at the telomeric imprinting control region 1 (ICR1) on 11p15 is an important cause of SRS.
  
  
  METHODS
  We studied the methylation pattern at the H19-IGF2 locus in 201 patients with suspected SRS. In an attempt to categorise the patients into different subgroups, we developed a simple clinical scoring system with respect to readily and unambiguously assessable clinical features. In a second step, the relationship between clinical score and epigenetic status was analysed.
  
  
  CONCLUSIONS
  The scoring system emerged as a powerful tool for identifying those patients with both a definite SRS phenotype and carrying an epimutation at 11p15. 53% of the 201 patients initially enrolled fulfilled the criteria for SRS and about 40% of them exhibited an epimutation at the H19-IGF2 locus. Methylation defects were restricted to patients who fulfilled the diagnostic criteria for SRS. Patients carrying epimutations had a more severe phenotype than either the SRS patients with mUPD7 or the idiopathic SRS patients. The majority of patients with methylation abnormalities showed hypomethylation at both the H19 and IGF2 genes. However, we also identified SRS patients where hypomethylation was restricted to either the H19 or the IGF2 gene. Interestingly, we detected epimutations in siblings of normal parents, most likely reflecting germ cell mosaicism in the fathers. In one family, we identified an epimutation in an affected father and his likewise affected daughter.
authors.forename: D
authors.initials: D
authors.lastname: Bartholdi
authors.forename: M
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: K
authors.initials: K
authors.lastname: Ounap
authors.forename: H
authors.initials: H
authors.lastname: Gaspar
authors.forename: K H
authors.initials: KH
authors.lastname: Chrzanowska
authors.forename: H
authors.initials: H
authors.lastname: Ilyana
authors.forename: H
authors.initials: H
authors.lastname: Kayserili
authors.forename: I W
authors.initials: IW
authors.lastname: Lurie
authors.forename: A
authors.initials: A
authors.lastname: Schinzel
authors.forename: A
authors.initials: A
authors.lastname: Baumer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019465:Craniofacial Abnormalities / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D012107:Research Design; D013577:Syndrome; D024182:Uniparental Disomy
chemical_list: C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II