1. ¹Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
2. ²University Hospitals, Geneva, Switzerland
3. ³Institute of Medical Genetics, Schwerzenbach, Switzerland
4. ⁴Cytogenetic Laboratory, General Hospital, Chambery, France
5. ⁵Department of Genetics, CHU Pellegrin, Bordeaux, France
6. ⁶Department of Genetics, IFR53 Reims, France
7. ⁷Department of Hematology, Reims Hospital, France
8. ⁸Département de Génétique Médicale, INSERM U781 Necker-Enfants Malades, Paris, France
9. ⁹Service de Génétique, CHU Hôpital Bretonneau, Tours, France
10. ¹⁰Institute of Human Genetics, University of Münster, Germany
11. ¹¹Department of Genetics, Institute for Developmental Research, Aichi, Japan
12. ¹²Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, UK
13. ¹³AlfaLAB, Molecular Biology and Cytogenetics Center, Athens, Greece
14. ¹⁴Department of Medical Genetics, University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
15. ¹⁵EA 3508 University Paris Denis Diderot, Paris, France
16. ¹⁶CNRS UMR7637, Paris, France

Correspondence: Dr R Lyle, Department of Medical Genetics, Ullevål University Hospital, Oslo 0407, Norway. Tel: +47 22 119 860; Fax: +47 22 119 899; E-mail: Robert.Lyle@medisin.uio.no; Professor SE Antonarakis, Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel-Servet, Geneva 1211, Switzerland. Tel: +41 22 379 5809; Fax: +41 22 702 5706; E-mail: Stylianos.Antonarakis@medecine.unige.ch

¹⁷Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway.

¹⁸Laboratory of Genetics, Foundation of Biomedical Research of the Academy of Athens, Athens, Greece.

Received 26 June 2008; Revised 3 September 2008; Accepted 10 October 2008; Published online 12 November 2008.

Abstract

Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype–phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within 85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.