title: High resolution array in the clinical approach to chromosomal phenotypes.
abstract: Array genomic hybridization (AGH) has recently been implemented as a diagnostic tool for the detection of submicroscopic copy number variants (CNVs) in patients with developmental disorders. However, there is no consensus regarding the choice of the platform, the minimal resolution needed and systematic interpretation of CNVs. We report our experience in the clinical diagnostic use of high resolution AGH up to 100 kb on 131 patients with chromosomal phenotypes but previously normal karyotype. We evaluated the usefulness in our clinics and laboratories by the detection rate of causal CNVs and CNVs of unknown clinical significance and to what extent their interpretation would challenge the systematic use of high-resolution arrays in clinical application. Prioritizing phenotype-genotype correlation in our interpretation strategy to criteria previously described, we identified 33 (25.2%) potentially pathogenic aberrations. 16 aberrations were confirmed pathogenic (16.4% syndromic, 8.5% non-syndromic patients); 9 were new and individual aberrations, 3 of them were pathogenic although inherited and one is as small as approx 200 kb. 13 of 16 further CNVs of unknown significance were classified likely benign, for 3 the significance remained unclear. High resolution array allows the detection of up to 12.2% of pathogenic aberrations in a diagnostic clinical setting. Although the majority of aberrations are larger, the detection of small causal aberrations may be relevant for family counseling. The number of remaining unclear CNVs is limited. Careful phenotype-genotype correlations of the individual CNVs and clinical features are challenging but remain a hallmark for CNV interpretation.
authors.forename: Isabel
authors.initials: I
authors.lastname: Filges
authors.forename: Luzia
authors.initials: L
authors.lastname: Suda
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Alexandre N
authors.initials: AN
authors.lastname: Datta
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
authors.forename: Patricia
authors.initials: P
authors.lastname: Dill
authors.forename: Réné
authors.initials: R
authors.lastname: Glanzmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Benzing
authors.forename: Lukas
authors.initials: L
authors.lastname: Hegi
authors.forename: Friedel
authors.initials: F
authors.lastname: Wenzel
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Huber
authors.forename: Andrea Capone
authors.initials: AC
authors.lastname: Mori
authors.forename: Peter
authors.initials: P
authors.lastname: Miny
authors.forename: Benno
authors.initials: B
authors.lastname: Röthlisberger
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics*; D002869:Chromosome Aberrations; D002877:Chromosomes, Human; D002658:Developmental Disabilities / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D009693:Nucleic Acid Hybridization / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D018092:Kainic Acid Receptors / Q000235:genetics; D000097806:GluK2 Kainate Receptor
chemical_list: D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor