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Different mutations in PDE4D associated with developmental disorders with mirror phenotypes
  1. Anna Lindstrand1,2,3,
  2. Giedre Grigelioniene1,2,3,
  3. Daniel Nilsson1,2,3,4,
  4. Maria Pettersson1,2,
  5. Wolfgang Hofmeister1,2,
  6. Britt-Marie Anderlid1,2,3,
  7. Sarina G. Kant5,
  8. Claudia A L Ruivenkamp5,
  9. Peter Gustavsson1,2,3,
  10. Helena Valta6,
  11. Stefan Geiberger7,
  12. Alexandra Topa8,
  13. Kristina Lagerstedt-Robinson1,2,3,
  14. Fulya Taylan1,2,4,
  15. Josephine Wincent1,2,3,
  16. Tobias Laurell1,2,9,
  17. Minna Pekkinen10,
  18. Magnus Nordenskjöld1,2,3,
  19. Outi Mäkitie1,2,3,6,10,
  20. Ann Nordgren1,2,3
  1. 1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  2. 2Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  3. 3Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  4. 4Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden
  5. 5Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
  7. 7Department of Pediatric Radiology, Karolinska University Hospital Solna, Stockholm, Sweden
  8. 8Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
  9. 9Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  10. 10Folkhälsan Institute of Genetics, Helsinki, Finland
  1. Correspondence to Dr Anna Lindstrand, and Ann Nordgren Department of Molecular Medicine and Surgery, Karolinska Institutet, Clinical Genetics Unit, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm S-171 76, Sweden; Anna.Lindstrand{at}


Background Point mutations in PDE4D have been recently linked to acrodysostosis, an autosomal dominant disorder with skeletal dysplasia, severe brachydactyly, midfacial hypoplasia and intellectual disability. The purpose of the present study was to investigate clinical and cellular implications of different types of mutations in the PDE4D gene.

Methods We studied five acrodysostosis patients and three patients with gene dose imbalances involving PDE4D clinically and by whole exome sequencing, Sanger sequencing and array comparative hybridisation. To evaluate the functional consequences of the PDE4D changes, we used overexpression of mutated human PDE4D message and morpholino-based suppression of pde4d in zebrafish.

Results We identified three novel and two previously described PDE4D point mutations in the acrodysostosis patients and two deletions and one duplication involving PDE4D in three patients suffering from an intellectual disability syndrome with low body mass index, long fingers, toes and arms, prominent nose and small chin. When comparing symptoms in patients with missense mutations and gene dose imbalances involving PDE4D, a mirror phenotype was observed. By comparing overexpression of human mutated transcripts with pde4d knockdown in zebrafish embryos, we could successfully assay the pathogenicity of the mutations.

Conclusions Our findings indicate that haploinsufficiency of PDE4D results in a novel intellectual disability syndrome, the 5q12.1-haploinsufficiency syndrome, with several opposing features compared with acrodysostosis that is caused by dominant negative mutations. In addition, our results expand the spectrum of PDE4D mutations underlying acrodysostosis and indicate that, in contrast to previous reports, patients with PDE4D mutations may have significant hormone resistance with consequent endocrine abnormalities.

  • Clinical Genetics
  • Copy-Number
  • Developmental
  • Other Neurology
  • Other Endocrinology

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