title: Mutations in HECW2 are associated with intellectual disability and epilepsy.
abstract: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.
  
  
  
  Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.
  
  
  
  In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.
  
  
  
  Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Halvardson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Jin J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Ammar
authors.initials: A
authors.lastname: Zaghlool
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Wentzel
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Georgii-Hemming
authors.affiliation: Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
authors.forename: Else
authors.initials: E
authors.lastname: Månsson
authors.affiliation: Department of Pediatrics, Gävle Hospital, Gävle, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Ederth Sävmarker
authors.affiliation: Pediatric Clinic, Falun, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Brandberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Soussi Zander
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
mesh_terms: D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D059472:Exome; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D013577:Syndrome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C574377:HECW2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ERC2; Epilepsy; Exome sequencing; HECW2; Intellectual disability