title: HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Hollstein
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nalbach
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK Yorkshire Regional Genetics Service, Leeds, UK.
authors.forename: Verity L
authors.initials: VL
authors.lastname: Hartill
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: Zentrum für Kinder- und Jugendmedizin, Neuropädiatrie, Klinikum Oldenburg, Oldenburg, Germany.
authors.forename: Georg C
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Uppal
authors.affiliation: Yorkshire Regional Genetics Service, Leeds, UK.
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.affiliation: Yorkshire Regional Genetics Service, Leeds, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bennett
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK Yorkshire Regional Genetics Service, Leeds, UK.
authors.forename: Eamonn G
authors.initials: EG
authors.lastname: Sheridan
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.affiliation: Section of Genetics, School of Medicine, University of Leeds, Leeds, UK Yorkshire Regional Genetics Service, Leeds, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics
chemical_list: C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Genetics