Diagnostic genome profiling in mental retardation.
Mental retardation (MR) occurs in 2%-3% of the general population. Conventional karyotyping has a resolution of 5-10 million bases and detects chromosomal alterations in approximately 5% of individuals with unexplained MR. The frequency of smaller submicroscopic chromosomal alterations in these patients is unknown. Novel molecular karyotyping methods, such as array-based comparative genomic hybridization (array CGH), can detect submicroscopic chromosome alterations at a resolution of 100 kb. In this study, 100 patients with unexplained MR were analyzed using array CGH for DNA copy-number changes by use of a novel tiling-resolution genomewide microarray containing 32,447 bacterial artificial clones. Alterations were validated by fluorescence in situ hybridization and/or multiplex ligation-dependent probe amplification, and parents were tested to determine de novo occurrence. Reproducible DNA copy-number changes were present in 97% of patients. The majority of these alterations were inherited from phenotypically normal parents, which reflects normal large-scale copy-number variation. In 10% of the patients, de novo alterations considered to be clinically relevant were found: seven deletions and three duplications. These alterations varied in size from 540 kb to 12 Mb and were scattered throughout the genome. Our results indicate that the diagnostic yield of this approach in the general population of patients with MR is at least twice as high as that of standard GTG-banded karyotyping.
de Vries
Bert B A
BB
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. b.devries@antrg.umcn.nl
Pfundt
Rolph
R
Leisink
Martijn
M
Koolen
David A
DA
Vissers
Lisenka E L M
LE
Janssen
Irene M
IM
Reijmersdal
Simon van
Sv
Nillesen
Willy M
WM
Huys
Erik H L P G
EH
Leeuw
Nicole de
Nd
Smeets
Dominique
D
Sistermans
Erik A
EA
Feuth
Ton
T
van Ravenswaaij-Arts
Conny M A
CM
van Kessel
Ad Geurts
AG
Schoenmakers
Eric F P M
EF
Brunner
Han G
HG
Veltman
Joris A
JA
D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D009693:Nucleic Acid Hybridization