title: Complex aetiology of an apparently Mendelian form of mental retardation.
abstract: BACKGROUND
  Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated.
  
  
  METHODS
  After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree.
  
  
  RESULTS
  No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status.
  
  
  CONCLUSIONS
  These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in the ongoing function of terminally differentiated neurons may underlie the phenotypic variation of intelligence and explain instances of intellectual impairment.
authors.affiliation: Department of Clinical Genetics, Rudbeck Laboratory, Uppsala University Hospital, Uppsala, Sweden. Karl-Henrik.Gustavson@genepat.uu.se
authors.forename: Ana
authors.initials: A
authors.lastname: Beleza-Meireles
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.forename: Qiu-Ping
authors.initials: QP
authors.lastname: Yuan
authors.forename: Simone
authors.initials: S
authors.lastname: Picelli
authors.forename: Lennart
authors.initials: L
authors.lastname: Wetterberg
authors.forename: Karl-Henrik
authors.initials: KH
authors.lastname: Gustavson
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
mesh_terms: D005260:Female; D018628:Gene Dosage; D008040:Genetic Linkage; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D005819:Genetic Markers