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X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face
  1. Magdalena Harakalova1,
  2. Marie-Jose van den Boogaard1,
  3. Richard Sinke2,
  4. Stef van Lieshout1,
  5. Marc C van Tuil1,
  6. Karen Duran1,
  7. Ivo Renkens1,
  8. Paulien A Terhal1,
  9. Carolien de Kovel1,
  10. Ies J Nijman1,
  11. Mieke van Haelst1,
  12. Nine V A M Knoers1,
  13. Gijs van Haaften1,
  14. Wigard Kloosterman1,
  15. Raoul C M Hennekam3,
  16. Edwin Cuppen1,4,
  17. Hans Kristian Ploos van Amstel1
  1. 1Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
  2. 2Department of Genetics, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands
  3. 3Department of Pediatrics, Academic Medical Center (AMC), Amsterdam, The Netherlands
  4. 4Hubrecht Institute, KNAW and University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
  1. Correspondence to Dr Hans Kristian Ploos van Amstel, Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht 3584 EA, The Netherlands; j.k.ploosvanamstel{at}


Background We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype.

Methods and results We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated.

Conclusions HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.

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  • ▸ Additional supplementary figures and tables are published online only. To view this file please visit the journal online (

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sector.

  • Competing interests None.

  • Patient consent Written informed consent was obtained from all study participants or their guardians and the study was approved at the recruiting centre.

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

  • Data sharing statement All bioinformatic scripts and pipelines are available upon request. Sequencing data are available (Sequence Read Archive accession number ERP001237).