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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.

SUBMITTER: Pelleri MC

PROVIDER: S-EPMC6687668 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Pelleri Maria Chiara MC Cicchini Elena E Petersen Michael B MB Tranebjaerg Lisbeth L Mattina Teresa T Magini Pamela P Antonaros Francesca F Caracausi Maria M Vitale Lorenza L Locatelli Chiara C Seri Marco M Strippoli Pierluigi P Piovesan Allison A Cocchi Guido G

Molecular genetics & genomic medicine 20190625 8

<h4>Background</h4>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 ide ...[more]

PMID: 31237416

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Project description:BackgroundDown 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.MethodsWe 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.ResultsClinical 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.ConclusionsThe 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.

Dataset Information

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

Publications

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

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