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Phenotypes
Short report
Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects
  1. Marjolein H Willemsen1,
  2. Lisenka E L Vissers1,2,
  3. Michèl A A P Willemsen3,
  4. Bregje W M van Bon1,
  5. Thessa Kroes1,2,
  6. Joep de Ligt1,2,
  7. Bert B de Vries1,
  8. Jeroen Schoots1,
  9. Dorien Lugtenberg1,
  10. Ben C J Hamel1,
  11. Hans van Bokhoven1,4,
  12. Han G Brunner1,2,
  13. Joris A Veltman1,2,
  14. Tjitske Kleefstra1
  1. 1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Nijmegen, The Netherlands
  3. 3Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Cognitive Neuroscience, Radboud University Nijmegen Medical centre, Nijmegen, The Netherlands
  1. Correspondence to Dr Tjitske Kleefstra, Radboud University Nijmegen Medical Centre, Department of Human Genetics, 849, PO Box 9101, Nijmegen 6500 HB, The Netherlands; t.kleefstra{at}gen.umcn.nl

Abstract

Background DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome.

Aim To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations.

Methods A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability.

Results In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described.

Conclusion Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.

  • DYNC1H1
  • intellectual disability
  • neuronal migration disorder
  • peripheral neuropathy
  • genetics
  • microRNA
  • neurosciences
  • chromosomal
  • copy-number
  • molecular genetics
  • microarray
  • metabolic disorders
  • rheumatoid arthritis
  • rheumatology
  • renal medicine
  • calcium and bone
  • diagnostics tests
  • genetic screening/counselling
  • visual development
  • clinical genetics
  • academic medicine
  • neuromuscular disease
  • memory disorders
  • hydrocephalus
  • cytogenetics

https://doi.org/10.1136/jmedgenet-2011-100542

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    Footnotes

    • MHW, LELMV contributed equally to this work.

    • Funding This work was supported by grants from the Consortium ‘Stronger on your own feet’ to TK and MHW, The Netherlands Organization for Health Research and Development (ZonMw grants 916-86-016 to LELMV, 917-66-363 and 911-08-025 to JAV, 917-86-319 to BBAdV, and 907-00-365 to TK), the EU-funded TECHGENE project (Health-F5-2009-223143 to JdL and JAV), the AnEuploidy project (LSHG-CT-2006-37627 to BWMvB and HGB, BBAdV and JAV), the GENCODYS, an EU FP7 large-scale integrating project grant (241995 to HvB and TK).

    • Competing interests None.

    • Ethics approval Local Medical Ethical Committee.

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

    • Data sharing statement The article is submitted as a short report, but additional data on the exome sequencing results in these patients, including an overview of all variants detected per proband and impact of the prioritisation steps for selecting candidate non-synonymous de novo mutations, are available upon request via the corresponding author.