title: Ade novo2.78-Mb duplication on chromosome 21q22.11 implicates candidate genes in the partial trisomy 21 phenotype.
abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) and in the majority of cases is the result of complete trisomy 21. The hypothesis that the characteristic DS clinical features are due to a single DS critical region (DSCR) at distal chromosome 21q has been refuted by recently reported segmental trisomy 21 cases characterised by microarray-based comparative genomic hybridisation (aCGH). These rare cases have implicated multiple regions on chromosome 21 in the aetiology of distinct features of DS; however, the map of chromosome 21 copy-number aberrations and their associated phenotypes remains incompletely defined. We report a child with ID who was deemed very high risk for DS on antenatal screening (1 in 13) and has partial, but distinct, dysmorphologic features of DS without congenital heart disease (CHD). Oligonucleotide aCGH testing of the proband detected a previously unreportedde novo2.78-Mb duplication on chromosome 21q22.11 that includes 16 genes; however, this aberration does not harbour any of the historical DSCR genes (APP,DSCR1,DYRK1AandDSCAM). This informative case implicates previously under-recognised candidate genes (SOD1,SYNJ1andITSN1) in the pathogenesis of specific DS clinical features and supports a critical region for CHD located more distal on chromosome 21q. In addition, this unique case illustrates how the increasing resolution of microarray and high-throughput sequencing technologies can continue to reveal new biology and enhance understanding of widely studied genetic diseases that were originally described over 50 years ago.
authors.affiliation: Division of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Medical Genetics Clinic, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Weisfeld-Adams
authors.affiliation: Medical Genetics Clinic, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Tkachuk
authors.affiliation: Division of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; The Linda Crnic Institute for Down Syndrome, University of Colorado, Aurora, CO, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Maclean
authors.affiliation: Division of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; Medical Genetics Clinic, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Meeks
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott