pubmed.ncbi.nlm.nih.gov

Recurrent copy number changes in mentally retarded children harbour genes involved in cellular localization and the glutamate receptor complex - PubMed

Recurrent copy number changes in mentally retarded children harbour genes involved in cellular localization and the glutamate receptor complex

Martin Poot et al. Eur J Hum Genet. 2010 Jan.

Abstract

To determine the phenotypic significance of copy number changes (CNCs) in the human genome, we performed genome-wide segmental aneuploidy profiling by BAC-based array-CGH of 278 unrelated patients with multiple congenital abnormalities and mental retardation (MCAMR) and in 48 unaffected family members. In 20 patients, we found de novo CNCs composed of multiple consecutive probes. Of the 125 probes making up these probably pathogenic CNCs, 14 were also found as single CNCs in other patients and 5 in healthy individuals. Thus, these CNCs are not by themselves pathogenic. Almost one out of five patients and almost one out of six healthy individuals in our study cohort carried a gain or a loss for any one of the recently discovered microdeletion/microduplication loci, whereas seven patients and one healthy individual showed losses or gains for at least two different loci. The pathogenic burden resulting from these CNCs may be limited as they were found with similar frequencies among patients and healthy individuals (P=0.165; Fischer's exact test), and several individuals showed CNCs at multiple loci. CNCs occurring specifically in our study cohort were enriched for components of the glutamate receptor family (GRIA2, GRIA4, GRIK2 and GRIK4) and genes encoding proteins involved in guiding cell localization during development (ATP1A2, GIRK3, GRIA2, KCNJ3, KCNJ10, KCNK17 and KCNK5). This indicates that disease cohort-specific compilations of CNCs may aid in identifying loci, genes and biological processes that contribute to the phenotype of patients.

PubMed Disclaimer

Figures

Figure 1
Figure 1

Flowchart of the data-triage procedure. For further explanation see text.

Figure 2
Figure 2

Recurrent CNCs specifically found in our MCAMR cohort. All CNCs mentioned in the DGV database have been omitted. Each dot represents a BAC probe according to its nucleotide position, following the March 2006 human reference sequence (NCBI Build 36.1). The ordinate position of each symbol represents the frequency of each CNC among MCAMR patients (closed symbol) and healthy individuals (open symbols). For each de novo loss and de novo gain found in our patients, red bars in the bottom decade and green bars in the top decade, respectively, have been added.

Similar articles

Cited by

References

    1. Newman WG, Hamilton S, Ayres J, et al. Array comparative genomic hybridization for diagnosis of developmental delay: an exploratory cost-consequences analysis. Clin Genet. 2007;71:254–259. - PubMed
    1. Ropers HH. X-linked mental retardation: many genes for a complex disorder. Curr Opin Genet Dev. 2006;16:260–269. - PubMed
    1. Lee JA, Lupski JR. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron. 2006;52:103–121. - PubMed
    1. Nielsen J, Wohlert M. Chromosome abnormalities found among 34 910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87:81–83. - PubMed
    1. Vissers LE, de Vries BB, Osoegawa K, et al. Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet. 2003;73:1261–1270. - PMC - PubMed

MeSH terms

Substances