Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

Abstract

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. We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we built an integrated, comparative map from 125 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. 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 is proposed as a candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has relevant homology only to the chimpanzee genome. Searching for HR-DSCR functional loci might become a priority for understanding the fundamental genotype-phenotype relationships in DS.

GeneBase 1.1: a tool to summarize data from NCBI gene datasets and its application to an update of human gene statistics

“…In addition, we show its usefulness for a systematic revision of the main reference parameters updated to January 2016 for a description of the human nuclear gene structure. Beyond the other possible applications described here, it might be useful to design experiments for poorly characterized annotated genome regions, as in our current annotation effort of the recently defined highly restricted Down Syndrome critical region (HR-DSCR) for example, which to date does not contain known genes (40) and is fundamental to understanding genotype–phenotype relationships of Down syndrome and for identifying new therapeutic approaches (41). This analysis finally paves the way for similar studies in other organisms, possibly providing new insight on gene and genome evolution.…”

Thrombocytopenia and Predisposition to Acute Myeloid Leukemia due to Mosaic Ring 21 with Loss of RUNX1: Cytogenetic and Molecular Characterization

“…Whether the ring was ever a single one cannot be determined from the published karyotype [Cavan et al, 2009] and seems unlikely. The fact that the distal portion of chromosome 21, where the critical region for Down syndrome is located (21q22.13), is present in a single copy in most cells may explain the lack of Down syndrome features [Pelleri et al, 2016].…”

A molecular view of the normal human thyroid structure and function reconstructed from its reference transcriptome map

“…The expression ratio, obtained from TRAM analysis, between the 2 genes is 1.098, consistent with a stoichiometric molecular ratio of 1:1 between proteins that work associated in a molecular complex. It would be interesting to deepen the functions of the overexpressed chr21 genes, to study them in relation to the pathogenesis of DS, and to search for new genes on chr21 (where there are only 273 known genes [33]) in light of the fact that a very small region apparently intergenic appears to be conserved in all subjects diagnosed with DS [34]. The study of pathogenesis of congenital hypothyrodism as well as of other alterations associated to DS will also take advantage of the just released transcriptomic atlas obtained by RNA-Seq method in 15 normal human embryo tissues and organs, among which is included the thyroid [35].…”