title: CTNND2-a candidate gene for reading problems and mild intellectual disability.
abstract: BACKGROUND
  Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.
  
  
  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.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hofmeister
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Topa
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Anderlid
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fahimeh
authors.initials: F
authors.lastname: Darki
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Matsson
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Isabel
authors.initials: I
authors.lastname: Tapia Páez
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Torkel
authors.initials: T
authors.lastname: Klingberg
authors.affiliation: Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Samuelsson
authors.affiliation: SciLifeLab, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Valtteri
authors.initials: V
authors.lastname: Wirta
authors.affiliation: SciLifeLab, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vezzi
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden Molecular Neurology Research Program, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Syk Lundberg
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D051177:Catenins / Q000235:genetics*; D002648:Child; D056905:Chromosome Breakpoints; D003071:Cognition; D005091:Exons / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011932:Reading; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic; D066127:White Matter / Q000473:pathology; D055815:Young Adult; D029961:Zebrafish Proteins / Q000235:genetics; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins; D000095002:Delta Catenin; C000722348:CTNND2 protein, human
keywords: Cell biology; Chromosomal; Copy-number; Memory Disorders; Molecular genetics