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.

Keywords: Down syndrome; computational biology; highly restricted Down syndrome critical region; human chromosome 21; intellectual disability; partial trisomy 21.

Figure 1

Array‐CGH analysis of DNA from patient MP01. Profile of chromosome 21 showing the duplication from 36,760,100 to 46,329,175 bases present in MP01 (reanalyzed case 1). Genomic coordinates refer to the current GRCh38 human assembly

Figure 2

Array‐CGH analysis of DNA from patient MP03. Profile of chromosome 21 showing the duplication from 14,112,687 to 28,015,203 bases present in MP03 (reanalyzed case 2). Genomic coordinates refer to the current GRCh38 human assembly

Figure 3

Array‐CGH analysis of DNA from patient #077. Profile of chromosomes 9 and 21 showing the duplication of chromosome 9 from 123,265,569 to 136,502,696 and from 137,666,340 to 138,059,636 bases and the duplication of chromosome 21 from 13,268,071 to 32,197,958 present in case #077 (reanalyzed case 3). Genomic coordinates refer to the current GRCh38 human assembly

Figure 4

Genotype–phenotype correlation in 132 cases of partial trisomy 21. The X‐axis displays the score for association with DS for each sequence interval of 50 kb, shown as median of the values assigned to each map row (Table S1) that is comprised in each interval. The Y‐axis represents the position along Hsa21 (scale in megabases, Mb)

Figure 5

Concise outlook (a) of a portion of the partial trisomy 21 map. Each column represents the chromosome 21 structure (in megabases, Mb) of partial trisomy 21 subjects with or without Down syndrome (DS or non‐DS). For each subject the case number (n.), the updated map identifier (ID) and the corresponding previous map ID if present (Pelleri et al., 2016) are reported. The ten cases reanalyzed or reviewed here are reported together with Map ID #116 and the duplication coded as structural variant nsv1060057 which delimited the proximal and distal highly restricted DS critical region (HR‐DSCR, red continuous line) boundaries, respectively. Red boxes, candidate or not excluded regions; green boxes, excluded regions; white boxes: information not available with certainty; blue boxes, monosomic regions. A zoom‐in (b) of the case (#116 here and #113 in the previous study (Pelleri et al., 2016)) and the CNV (nsv1060057) strictly defining HR‐DSCR limits are shown here. Rows: Hsa21 sequence intervals (only those centered on HR‐DSCR are represented here). Red = candidate or not excluded regions; green = excluded regions. Levels of overlapping among intervals are indicated by increasingly darker violet color of the coordinates; blue italics indicate coordinates overlapping (Start or End) or nesting (Start and End) with the immediately previous interval (row). HR‐DSCR coordinates: 37,929,229–37,963,130. Complete map is available as Table S1