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Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
  1. T Kleefstra1,
  2. W A van Zelst-Stams2,
  3. W M Nillesen1,
  4. V Cormier-Daire3,
  5. G Houge4,
  6. N Foulds5,
  7. M van Dooren6,
  8. M H Willemsen1,
  9. R Pfundt1,
  10. A Turner7,
  11. M Wilson8,
  12. J McGaughran9,
  13. A Rauch10,
  14. M Zenker10,
  15. M P Adam11,
  16. M Innes12,
  17. C Davies12,
  18. A González-Meneses López13,
  19. R Casalone14,
  20. A Weber15,
  21. L A Brueton16,
  22. A Delicado Navarro17,
  23. M Palomares Bralo17,
  24. H Venselaar18,
  25. S P A Stegmann2,
  26. H G Yntema1,
  27. H van Bokhoven1,
  28. H G Brunner1
  1. 1
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2
    Department of Human Genetics, Maastricht University Hospital, Maastricht, The Netherlands
  3. 3
    Department of Medical Genetics and INSERM U781, Hôpital Necker Enfants Malades, Paris, France
  4. 4
    Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  5. 5
    Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
  6. 6
    Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
  7. 7
    Department of Medical Genetics, Sydney Children’s Hospital, Randwick, Sydney, Australia
  8. 8
    Department of Clinical Genetics, Children’s Hospital at Westmead, Sydney, Australia
  9. 9
    Genetic Health Queensland, Royal Children’s Hospital and Health District, Herston, Brisbane, Queensland, Australia
  10. 10
    Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
  11. 11
    Emory University, Atlanta, Georgia, USA
  12. 12
    Department of Clinical Genetics, Alberta Children’s Hospital, Calgary, Canada
  13. 13
    Unidad de Dismorfología, Servicio de Pediatría, Hospital Universitario Virgendel Rocío, Sevilla, Spain
  14. 14
    Dipartimento di Patologia Clinica, S.S. di Genetica Medica, Azienda Ospedaliero Universitaria, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
  15. 15
    Alder Hey Children’s Hospital, Liverpool, UK
  16. 16
    Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham, UK
  17. 17
    Sección de Genética Médica, Hospital Universitario La Paz, Madrid, Spain
  18. 18
    Center for Molecular and Biomolecular Informatics, Radboud University Nijmegen, The Netherlands.
  1. Correspondence to Dr T Kleefstra, 849 Department of Human Genetics, PO Box 9101, 6500 HB Nijmegen, The Netherlands; t.kleefstra{at}


Background: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far.

Methods and results: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein.

Conclusions: The data do not provide any evidence for phenotype–genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.

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  • Competing interests None declared.

  • Patient consent Obtained.

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