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A Common Molecular Mechanism Underlies Two Phenotypically Distinct 17p13.1 Microdeletion Syndromes |
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| Authors: | Adam Shlien Berivan Baskin Dimitrios J Stavropoulos Kim E Nichols Chantal F Morel Nataliya Zhukova Ana Novokmet Mary Shago Pierre Hainaut |
| Institution: | 1 Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada 2 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1X8, Canada 3 Division of Molecular Genetics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada 4 Hospital A.C. Camargo, 01509-010 São Paulo, Brazil 5 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G1X8, Canada 6 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA 7 Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA 8 Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G1X8, Canada 9 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30033, USA 10 Division of Hematology/Oncology, The Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada 11 Department of Molecular Genetics, The University of Toronto, Toronto, ON M5G1X8, Canada 12 Molecular Carcinogenesis and Biomarkers Group, International Agency for Research on Cancer, 69372 Lyon, France |
| Abstract: | DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature. |
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