Portal de Periódicos da CAPES

Diagnostic Genome Profiling in Mental Retardation

2005; Elsevier BV; Volume: 77; Issue: 4 Linguagem: Inglês

10.1086/491719

1537-6605

Bert B.A. de Vries, Rolph Pfundt, M.A.R. Leisink, David A. Koolen, Lisenka E.L.M. Vissers, Irene M. Janssen, Simon V. van Reijmersdal, Willy M. Nillesen, Erik Huys, Nicole de Leeuw, Dominique Smeets, Erik A. Sistermans, Ton Feuth, Conny M.A. van Ravenswaaij‐Arts, Ad Geurts van Kessel, Eric Schoenmakers, Han G. Brunner, Joris A. Veltman,

Genetics and Neurodevelopmental Disorders

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 ∼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. 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 ∼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.