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

Maria Chiara Pelleri; Elena Cicchini; Michael B. Petersen; Lisbeth Tranebjærg; Teresa Mattina; Pamela Magini; Francesca Antonaros; Maria Caracausi; Lorenza Vitale; Chiara Locatelli; Marco Seri; Pierluigi Strippoli; Allison Piovesan; Guido Cocchi

doi:10.1002/mgg3.797

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

Maria Chiara Pelleri, Elena Cicchini, Michael B. Petersen, Lisbeth Tranebjærg, Teresa Mattina, Pamela Magini, Francesca Antonaros, Maria Caracausi, Lorenza Vitale, Chiara Locatelli, Marco Seri, Pierluigi Strippoli, Allison Piovesan^*, Guido Cocchi

^*Corresponding author for this work

Department of Clinical Medicine

8 Citations (Scopus)

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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.

Original language	English
Article number	e797
Journal	Molecular Genetics & Genomic Medicine
Volume	7
Number of pages	14
ISSN	2324-9269
DOIs	https://doi.org/10.1002/mgg3.797
Publication status	Published - Aug 2019

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Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21Final published version, 1.65 MBLicence: CC BY

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Pelleri, M. C., Cicchini, E., Petersen, M. B., Tranebjærg, L., Mattina, T., Magini, P., Antonaros, F., Caracausi, M., Vitale, L., Locatelli, C., Seri, M., Strippoli, P., Piovesan, A., & Cocchi, G. (2019). Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21. Molecular Genetics & Genomic Medicine, 7, [e797]. https://doi.org/10.1002/mgg3.797

Pelleri, MC, Cicchini, E, Petersen, MB, Tranebjærg, L, Mattina, T, Magini, P, Antonaros, F, Caracausi, M, Vitale, L, Locatelli, C, Seri, M, Strippoli, P, Piovesan, A & Cocchi, G 2019, 'Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21', Molecular Genetics & Genomic Medicine, vol. 7, e797. https://doi.org/10.1002/mgg3.797

@article{5850af7d21db4b9c8c5eea37fd3ed590,

title = "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.",

author = "Pelleri, {Maria Chiara} and Elena Cicchini and Petersen, {Michael B.} and Lisbeth Tranebj{\ae}rg and Teresa Mattina and Pamela Magini and Francesca Antonaros and Maria Caracausi and Lorenza Vitale and Chiara Locatelli and Marco Seri and Pierluigi Strippoli and Allison Piovesan and Guido Cocchi",

note = "Funding information: MCP's fellowship has been co‐funded by a donation from Fondazione Umano Progresso, Milano, Italy and by donations following the international fundraising initiative by Vittoria Aiello and Massimiliano Albanese. The fellowship for EC has been funded by Centro Universitario Cattolico, Italy. The fellowship for FA has been funded by Illumia S.p.A. (Bologna, Italy). The fellowships for MC and AP have been funded by the Fondazione Umano Progresso, Matteo and Elisa Mele and Radius S.r.l.—Technology for life (www.radiustech.it). ",

year = "2019",

month = aug,

doi = "10.1002/mgg3.797",

language = "English",

volume = "7",

journal = "Molecular Genetics & Genomic Medicine",

issn = "2324-9269",

publisher = "JohnWiley & Sons Ltd",

}

TY - JOUR

T1 - Partial trisomy 21 map

T2 - Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21

AU - Pelleri, Maria Chiara

AU - Cicchini, Elena

AU - Petersen, Michael B.

AU - Tranebjærg, Lisbeth

AU - Mattina, Teresa

AU - Magini, Pamela

AU - Antonaros, Francesca

AU - Caracausi, Maria

AU - Vitale, Lorenza

AU - Locatelli, Chiara

AU - Seri, Marco

AU - Strippoli, Pierluigi

AU - Piovesan, Allison

AU - Cocchi, Guido

N1 - Funding information: MCP's fellowship has been co‐funded by a donation from Fondazione Umano Progresso, Milano, Italy and by donations following the international fundraising initiative by Vittoria Aiello and Massimiliano Albanese. The fellowship for EC has been funded by Centro Universitario Cattolico, Italy. The fellowship for FA has been funded by Illumia S.p.A. (Bologna, Italy). The fellowships for MC and AP have been funded by the Fondazione Umano Progresso, Matteo and Elisa Mele and Radius S.r.l.—Technology for life (www.radiustech.it).

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

U2 - 10.1002/mgg3.797

DO - 10.1002/mgg3.797

M3 - Journal article

C2 - 31237416

SN - 2324-9269

VL - 7

JO - Molecular Genetics & Genomic Medicine

JF - Molecular Genetics & Genomic Medicine

M1 - e797

ER -

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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