Microdeletion encompassing the MAPT gene at chromosome 17q21.3 is associated with developmental delay and learning disability. C. Shaw-Smith¹, A. Pittman², L. Willatt³, H. Martin⁴, L. Rickman⁵, S. Gribble⁵, R. Curley⁵, S. Cumming⁴, C. Dunn³, D. Kalaitzopoulos⁵, K. Porter⁵, E. Prigmore⁵, A. Krepischi-Santos⁶, M. Varela⁷, C. Koiffman⁷, A. Lees², C. Rosenberg⁶, H.V. Firth¹, R. de Silva², N.P. Carter⁵. 1) Medical Genetics, University of Cambridge, Cambridge, United Kingdom; 2) Reta Leila Weston Institute of Neurological Studies, University College, London UK; 3) Regional Cytogenetics Laboratory, Addenbrooke's Hospital, Cambridge, UK; 4) Regional Molecular Genetics Laboratory, Addenbrooke's Hospital, UK; 5) Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; 6) Department of Genetics and Evolutionary Biology, Institute of Biosciences, Sao Paulo, Brazil; 7) Human Genome Study Centre, Department of Genetics and Evolutionary Biology, University of Sao Paulo, Brazil.
   Recently, the application of array-based comparative genomic hybridization (array-CGH) has improved rates of detection of chromosomal imbalances in patients with mental retardation. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array-CGH. There are some clinical similarities between the three patients: low birth-weight, neonatal hypotonia and feeding difficulties were present in each case, as well as moderate to severe learning difficulties. FISH analysis demonstrated that the deletions occurred as de novo events in each patient and were between 500 kb and 650 kb in size. A recently described 900 kb inversion which suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 exhibits complexity of genomic architecture with well-described low copy repeats (LCRs). We show that the orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by the mechanism of non-allelic homologous recombination. We believe this to be the first microdeletion syndrome to be described in which all the patients have been ascertained by array-CGH.