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  • A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features

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Neurogenetics
Short Report
A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features
  1. Isaac Marin-Valencia1,
  2. Gaia Novarino1,2,
  3. Anide Johansen3,4,
  4. Basak Rosti1,3,4,
  5. Mahmoud Y Issa5,
  6. Damir Musaev3,4,
  7. Gifty Bhat1,
  8. Eric Scott3,4,
  9. Jennifer L Silhavy3,4,
  10. Valentina Stanley3,4,
  11. Rasim O Rosti1,3,4,
  12. Jeremy W Gleeson3,4,
  13. Farhad B Imam6,
  14. Maha S Zaki5,
  15. Joseph G Gleeson1,3,4
  1. 1 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA
  2. 2 Institute of Science and Technology Austria (IST), Klosterneuburg, Niederösterreich, Austria
  3. 3 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, La Jolla, California, USA
  4. 4 Rady Children’s Institute for Genomic Medicine, Rady Children’s Hospital, San Diego, California, USA
  5. 5 Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
  6. 6 Department of Pediatrics, University of California, San Diego, California, USA
  1. Correspondence to Dr Joseph G Gleeson, Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, USA; jogleeson{at}ucsd.edu; dr_mahazaki{at}yahoo.com

Abstract

Background Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.

Objective We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.

Methods Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.

Results We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.

Conclusion This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.

  • TRAPPC6B
  • TRAPP complex
  • intellectual disability
  • autism
  • epilepsy
  • microcephaly

https://doi.org/10.1136/jmedgenet-2017-104627

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    Footnotes

    • Contributors IMV, MZ and JGG designed the study. IMV, GN, AJ, BR, JWG and IF performed experiments and analysis. JWG and IF participated in data interpretation and analysis of zebrafish data. IMV, MI, GB, VS, OR, MZ and JGG participated in recruiting patients, gathering clinical information and described the clinical phenotype. IMV, GN, AJ, GB, MZ and JGG wrote the manuscript. MZ and JGG supervised the project.

    • Funding IM–V was sponsored by Pilot Grant awarded by the Center for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University through the generosity of the Leona M and Harry B. Helmsley Charitable Trust. The authors thank the Broad Institute and Yale Mendelian Sequencing Effort. They thank the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel). This work was supported by NIH grants P01HD070494, R01NS048453, R01NS052455, P01HD070494, the Simons Foundation Autism Research Initiative and Howard Hughes Medical Institute (to JGG and GN).

    • Competing interests None declared.

    • Patient consent Consent obtained from guardian.

    • Ethics approval The study was consistent with Institutional Review Board guidelines and approved by the ethical committees of UC San Diego.

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