Article Text

PDF
Original article
CTNND2—a candidate gene for reading problems and mild intellectual disability
  1. Wolfgang Hofmeister1,2,
  2. Daniel Nilsson1,2,3,4,
  3. Alexandra Topa5,
  4. Britt-Marie Anderlid1,2,3,
  5. Fahimeh Darki6,
  6. Hans Matsson7,
  7. Isabel Tapia Páez7,
  8. Torkel Klingberg6,
  9. Lena Samuelsson5,
  10. Valtteri Wirta8,
  11. Francesco Vezzi9,
  12. Juha Kere7,10,
  13. Magnus Nordenskjöld1,2,3,
  14. Elisabeth Syk Lundberg1,2,3,
  15. Anna Lindstrand1,2,3
  1. 1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  2. 2Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  3. 3Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  4. 4Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden
  5. 5Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
  6. 6Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  7. 7Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden
  8. 8SciLifeLab, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden
  9. 9SciLifeLab, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
  10. 10Molecular Neurology Research Program, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland
  1. Correspondence to Dr Anna Lindstrand, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm S-171 76, Sweden; Anna.Lindstrand{at}ki.se

Abstract

Background Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.

Methods and results Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.

Conclusions Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.

  • Chromosomal
  • Copy-number
  • Molecular genetics
  • Memory Disorders
  • Cell biology

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.