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Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome
  1. H Vega1,2,
  2. A H Trainer3,
  3. M Gordillo1,
  4. M Crosier3,
  5. H Kayserili4,
  6. F Skovby5,
  7. M L Giovannucci Uzielli6,
  8. R E Schnur7,
  9. S Manouvrier8,
  10. E Blair9,
  11. J A Hurst9,
  12. F Forzano10,
  13. M Meins11,
  14. K O J Simola12,
  15. A Raas-Rothschild13,
  16. R C M Hennekam14,15,
  17. E Wang Jabs1
  1. 1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of City University of New York, New York, USA
  2. 2Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia
  3. 3MRC-Wellcome Trust Human Developmental Biology Resource, Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
  4. 4Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
  5. 5Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark
  6. 6Genetics and Molecular Medicine Unit, Department of Paediatrics, University of Florence, Florence, Italy
  7. 7Department of Pediatrics, Cooper University Hospital/Robert Wood Johnson Medical School, Camden, New Jersey, USA
  8. 8Department of Clinical Genetics, University Hospital, Lille, France
  9. 9Department of Clinical Genetics, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Oxford, UK
  10. 10SC Genetica Umana, Ospedali Galliera, Genova, Italy
  11. 11Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany
  12. 12Department of Pediatrics, Tampere University Hospital, Tampere, Finland
  13. 13Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel
  14. 14Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK
  15. 15Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr H Vega, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of City University of New York, New York, NY 10029, USA; hhvegaf{at}


Background Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype–phenotype analysis has been hampered by limited numbers of patients with clinical information available.

Objective To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases.

Methods Genotype–phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development.

Results and conclusions Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.

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  • Additional tables and figures are published online only at

  • Funding EWJ was supported by the Louis H Gross Foundation and L and S Pakula.

  • Competing interests None.

  • Ethics approval Ethics committee approval was obtained from Johns Hopkins University, Mount Sinai School of Medicine, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Newcastle University, Universidad Nacional de Colombia, Istanbul University and University of Amsterdam.

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