A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes.

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 break point 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