Recurrent copy number changes in mentally retarded children harbour genes involved in cellular localization and the glutamate receptor complex.
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.
Poot
Martin
M
Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, Mail stop: KC.04.084.2, Utrecht, 3508 AB, The Netherlands. m.poot@umcutrecht.nl
Eleveld
Marc J
MJ
van 't Slot
Ruben
R
Ploos van Amstel
Hans Kristian
HK
Hochstenbach
Ron
R
D002648:Child; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D021381:Protein Transport; D017470:Receptors, Glutamate / Q000235:genetics*
D017470:Receptors, Glutamate