Highly restricted Down syndrome critical region identified on human chromosome 21.

Introduction: A „Down Syndrome critical region“ (DSCR) sufficient to induce the most constant phenotypes of Down syndrome (DS) had been identified by studying partial (segmental) trisomy 21 (PT21) as an interval of 0.6-8.3 Mb within human chromosome 21 (Hsa21), although its existence was later questioned. Materials and Methods: We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we build an integrated, comparative map from 126 cases with or without DS fulfilling stringent cytogenetic and clinical criteria. The map allowed to define or exclude as candidates for DS fine Hsa21 sequence intervals, also integrating duplication copy number variants (CNVs) data. Results: A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects. Also being spared by any duplication CNV in healthy subjects, HR-DSCR represents a strong candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has homology only to the chimpanzee genome. Conclusion: Our results strongly support the view that a single main critical region for DS actually exists, that it appears to be much smaller than previously suspected and that it could contain currently undescribed genes whose identification should become a priority for understanding the fundamental genotype-phenotype relationships in DS and in searching for highly relevant targets for a cure of DS.