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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.
  1. Deborah Bartholdi (debobarth{at}yahoo.com)
  1. Institute of Medical Genetics, University of Zürich, Schwerzenbach, Switzerland
    1. Malgorzata Krajewska-Walasek
    1. Department of Medical Genetics, The Children’s Memorial Health Institute, University of Warsaw, Poland
      1. Katrin Õunap
      1. Department of Genetics, Tartu University Hospital and Department of Pediatrics, Tartu University, Estonia
        1. Harald Gaspar
        1. Institute of Medical Genetics, University of Zürich, Schwerzenbach, Switzerland
          1. Krystyna H Chrzanowska
          1. Department of Medical Genetics, The Children’s Memorial Health Institute, University of Warsaw, Poland
            1. Helena Ilyana
            1. Belorussian Research Institute of Hereditary Diseases, Minsk, Belarus
              1. Hülya Kayserili
              1. Institute of Child Health, Division of Medical Genetics, Istanbul University, Turkey
                1. Iosif W Lurie
                1. Belorussian Research Institute of Hereditary Diseases, Minsk, Belarus
                  1. Albert Schinzel
                  1. Institute of Medical Genetics, University of Zürich, Schwerzenbach, Switzerland
                    1. Alessandra Baumer
                    1. Institute of Medical Genetics, University of Zürich, Schwerzenbach, Switzerland

                      Abstract

                      Background: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous condition characterized 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 categorize 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 analyzed.

                      Results and 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.

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