Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): report of two new cases and reanalysis of the genotype-phenotype association

Abstract

Background: Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype-phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed 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.

Methods: We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report.

Results: Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype-phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals.

Conclusions: The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability.

Keywords: Down syndrome; Highly restricted Down syndrome critical region; Partial trisomy 21.

Fig. 1

Picture of Case 2 showing her face (a), hands (b) and left foot (c). She does not show the Down syndrome recognizable phenotype

Fig. 2

Array-CGH analysis of DNA from Case 1 showing the alteration of chromosome 21 (chr21): arr[GRCh38] 21q11.2q22.3(14145727_43860444) × 3,21q22.3(43927315_46670405) × 1. In the present study genomic coordinates were converted to the matching current coordinates on hg38 using the online tool LiftOver (https://genome.ucsc.edu/cgi-bin/hgLiftOver) so the figure shows the duplication of chromosome 21 from 14,145,727 to 43,860,444 bp and the deletion from 43,927,315 to 46,670,405 bp (GRCh38). The HR-DSCR (chr21 from 37,929,229 to 37,963,130) is within the duplicated regions

Fig. 3

Array-CGH analysis of DNA from Case 2 showing the alteration of chromosome 20 and 21: [GRCh38] 20p13(87137_2197493) × 1, 21q22.2q22.3(39502312_46670405) × 3. In the present study genomic coordinates were converted to the matching current coordinates on hg38 using the online tool LiftOver (https://genome.ucsc.edu/cgi-bin/hgLiftOver). A Array-CGH analysis showing the deletion of chromosome 20 (chr20) from 87,137 to 2,197,493 bp (GRCh38). B Array-CGH analysis the duplication of chromosome 21 (chr21) from 14,145,727 to 43,860,444 bp and the deletion from 43,927,315 to 46,670,405 bp (GRCh38). The HR-DSCR (chr21 from 37,929,229 to 37,963,130) is not duplicated

Fig. 4

HR-DSCR as highlighted by the partial trisomy 21 integrated map (simplified view). The cases described in the present work are shown (Cases 1, 2, 3, 4); moreover, the cases (#059, #105 and #113, intellectual disability used in [12] and the copy number variant (CNV, nsv1060057, from Database of Genomic Variants, http://dgv.tcag.ca/) strictly defining HR-DSCR limits are shown here. Light grey bar: disomic region; dark grey bar: trisomic region: Blue bar: monosomic region. Case n. 1 (this work); Case n. 2 (this work); Case n. 3 [19]; Case n. 4 [20]; #059: Case DUP21SOL [8]; #105: [29]; #113: Case DUP21HAD [8]. DS: subject with Down syndrome; non-DS: subject without Down syndrome