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Submicroscopic genomic alterations in Silver–Russell syndrome and Silver–Russell-like patients
  1. Sara Bruce1,2,
  2. Katariina Hannula-Jouppi2,
  3. Mari Puoskari1,2,
  4. Ingegerd Fransson1,
  5. Kalle O J Simola3,
  6. Marita Lipsanen-Nyman4,
  7. Juha Kere1,2
  1. 1Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
  2. 2Department of Medical Genetics, University of Helsinki, and Folkhälsan Institutet of Genetics, Helsinki, Finland
  3. 3Department of Pediatrics, Tampere University Hospital, Tampere, Finland
  4. 4Hospital for Children and Adolescents, University of Helsinki, Finland
  1. Correspondence to Dr Sara Bruce, Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7-9, Huddinge, Sweden; sara.bruce{at}ki.se

Abstract

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.

  • Silver-Russell syndrome
  • copy number
  • genomic screen
  • IGF1R deletion
  • atypical distal 22q11.2 deletion
  • endocrinology
  • genetic screening
  • molecular genetics

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Footnotes

  • Funding This work was supported by Magn Bergvalls stiftelse, the Swedish Research Council, Päivikki and Sakari Sohlberg Foundation, Sigrid Juselius Foundation, Helsinki University Hospital research funds, Finnish Foundation for Pediatric Research, and the Academy of Finland.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the ethics review board of the Hospital for Children and Adolescents, University of Helsinki, Finland and Karolinska Institutet, Sweden

  • Provenance and peer review Not commissioned; externally peer reviewed.

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