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Original article
HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome
  1. Ronja Hollstein1,
  2. David A Parry2,
  3. Lisa Nalbach1,
  4. Clare V Logan2,
  5. Tim M Strom3,4,
  6. Verity L Hartill2,5,
  7. Ian M Carr2,
  8. Georg C Korenke6,
  9. Sandeep Uppal2,
  10. Mushtaq Ahmed5,
  11. Thomas Wieland4,
  12. Alexander F Markham2,
  13. Christopher P Bennett5,
  14. Gabriele Gillessen-Kaesbach7,
  15. Eamonn G Sheridan2,5,
  16. Frank J Kaiser1,
  17. David T Bonthron2,5
  1. 1Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
  2. 2Section of Genetics, School of Medicine, University of Leeds, Leeds, UK
  3. 3Institute of Human Genetics, Technische Universität München, Munich, Germany
  4. 4Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
  5. 5Yorkshire Regional Genetics Service, Leeds, UK
  6. 6Zentrum für Kinder- und Jugendmedizin, Neuropädiatrie, Klinikum Oldenburg, Oldenburg, Germany
  7. 7Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
  1. Correspondence to Professor David Bonthron, Section of Genetics, Wellcome Trust Brenner Building, L9, St James's University Hospital, Leeds LS9 7TF, UK; d.t.bonthron{at} or Prof Dr Frank Kaiser, Sektion für Funktionelle Genetik am Institut für Humangenetik, Ratzeburger Allee 160, 23562 Lübeck, Germany; Frank.Kaiser{at}


Background The genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait.

Methods Autosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene.

Results In both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic homologous to the E6-AP carboxyl terminus (HECT) domain was present; western blot analysis of patient cells revealed an absence of detectable HACE1 protein.

Conclusion HACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re-evaluation.

  • Genetics

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