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Mutations in HECW2 are associated with intellectual disability and epilepsy
  1. Jonatan Halvardson1,
  2. Jin J Zhao1,
  3. Ammar Zaghlool1,
  4. Christian Wentzel1,
  5. Patrik Georgii-Hemming1,2,
  6. Else Månsson3,
  7. Helena Ederth Sävmarker4,
  8. Göran Brandberg5,
  9. Cecilia Soussi Zander1,
  10. Ann-Charlotte Thuresson1,
  11. Lars Feuk1
  1. 1Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden
  2. 2Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden
  3. 3Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
  4. 4Department of Pediatrics, Gävle Hospital, Gävle, Sweden
  5. 5Pediatric Clinic, Falun, Sweden
  1. Correspondence to Dr Lars Feuk, Department of Immunology, Genetics and Pathology, Box 815, BMC B11:4, Uppsala University, SE-751 08 Uppsala, Sweden; lars.feuk{at}igp.uu.se

Abstract

Background 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.

Methods 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.

Results 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.

Conclusions 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.

  • Intellectual disability
  • Epilepsy
  • Exome sequencing
  • HECW2
  • ERC2

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