Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21

Abstract

Background Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype‐phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34‐kb highly restricted DS critical region (HR‐DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR‐DSCR limits could prospectively be confirmed and possibly refined. Methods Hsa21 partial duplications of three PT21 subjects were refined by adding array‐based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map. Results The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR‐DSCR, on distal 21q22.13 sub‐band, only in DS subjects and not in non‐DS individuals. No documented exception to the HR‐DSCR model was found. Conclusions The findings presented here further support the association of the HR‐DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR‐DSCR and functionally associated to the critical manifestations of DS.

The transcriptome profile of human trisomy 21 blood cells

“…FPKM values for each sample are tabulated in Supplementary Table 2 . No read map in the HR-DSCR [ 4 ].…”

“…Down syndrome (DS) is the most common form of intellectual disability (ID) of genetic origin in humans [ 1 , 2 ]. Also known as trisomy 21, it is caused by the presence of an extra full or partial (partial T21, PT21) human chromosome 21 (Hsa21) [ 3 , 4 ] in the cells of the affected subjects. Recently, the identification of a highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is associated to DS because it is shared by all subjects with PT21 diagnosed with DS was confirmed [ 4 ].…”

One-carbon pathway and cognitive skills in children with Down syndrome

“…Down syndrome (DS) [MIM: 190685] is caused by an extra copy of all 1 or even a small part of 2 human chromosome 21 (Hsa21) and it is the most common genetic cause of intellectual disability (ID). Hsa21 gene expression in cells and tissues from subjects with DS has been reported as altered 3 and recently associated with changes in the metabolic profile that might be involved in the development of the clinical features 4 .…”

Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome

“…In recent years, AD has been increasingly understood as a metabolic disease, 63 necessarily implicating structures beyond the CNS. This is certainly applicable to DS, which is marked by substantially elevated, genetically penetrant risk for both AD and type 1 diabetes 113–115 . It is similarly reflected in the variety of biomolecules recently implicated in AD via metabolomics approaches.…”