Complete chromosome 21 centromere sequencing of families with Down syndrome
9 affiliations
- 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
- 2Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70124 Bari, Italy
- 3Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- 4Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
- 5Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada
- 6Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
- 7Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- 8Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected]
- 9Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected]
Abstract
Down syndrome, the most common form of human intellectual disability, results from nondisjunction and an extra copy of chromosome 21 (chr21), also known as trisomy 21 (T21). Small centromeres have been hypothesized to contribute to its etiology, and studies on mice suggest that larger centromeres are more efficiently transmitted, yet complete sequencing of chr21 centromeres has been particularly challenging due to their repetitive nature and homology to chromosome 13. Using long-read sequencing, we sequenced and assembled the centromeres from eight families with a child with T21 (one parent-child trio, six mother-child duos, and one singleton), all resulting from maternal meiosis I errors. A comparison of all proband chr21 centromeres (n = 24) to those of control individuals (n = 287) shows that small centromeres are not enriched in families with T21 (p value = 0.72), contrary to earlier reports. However, chr21 extreme centromere size asymmetry (>10-fold) was observed for two of them. Mothers from these two families with T21 carry some of the smallest chr21 centromeres (143 and 181 kbp) observed in female individuals to date, exhibiting a ∼10.7- and ∼19.4-fold centromeric α-satellite higher-order repeat array size difference between the maternally inherited homologs, respectively. Phylogenetic reconstruction reveals that human chr21 is particularly prone to such asymmetry, with some of the biggest size differences occurring over the last ∼17,000 years of human evolution.
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BibTeX
@article{mastrorosa2026complete,
title = {{Complete chromosome 21 centromere sequencing of families with Down syndrome}},
author = {Francesco Kumara Mastrorosa and Alessia Daponte and Luciana de Gennaro and Shu-Cheng Chuang and Jiadong Lin and Yang Sui and David Porubskỳ and Keisuke K. Oshima and Julie Wertz and Allison N. Rozanski and William T. Harvey and Yanni Wang and Tiffany Y. Leung and Daniel D. Chan and Weiya He and Jordan Knuth and Gage H. Garcia and Marcelo Ayllon and Katherine M. Munson and Kendra Hoekzema and Peter M. Lansdorp and Claudia Rita Catacchio and Mario Ventura and Stephanie L. Sherman and Emily Graves Allen and Tracie C. Rosser and Glennis A. Logsdon and Evan E. Eichler},
journal = {The American Journal of Human Genetics},
year = {2026},
month = jun,
doi = {10.1016/j.ajhg.2026.05.010},
url = {https://doi.org/10.1016/j.ajhg.2026.05.010},
note = {CC BY},
}
RIS
TY - JOUR
TI - Complete chromosome 21 centromere sequencing of families with Down syndrome
AU - Francesco Kumara Mastrorosa
AU - Alessia Daponte
AU - Luciana de Gennaro
AU - Shu-Cheng Chuang
AU - Jiadong Lin
AU - Yang Sui
AU - David Porubskỳ
AU - Keisuke K. Oshima
AU - Julie Wertz
AU - Allison N. Rozanski
AU - William T. Harvey
AU - Yanni Wang
AU - Tiffany Y. Leung
AU - Daniel D. Chan
AU - Weiya He
AU - Jordan Knuth
AU - Gage H. Garcia
AU - Marcelo Ayllon
AU - Katherine M. Munson
AU - Kendra Hoekzema
AU - Peter M. Lansdorp
AU - Claudia Rita Catacchio
AU - Mario Ventura
AU - Stephanie L. Sherman
AU - Emily Graves Allen
AU - Tracie C. Rosser
AU - Glennis A. Logsdon
AU - Evan E. Eichler
PY - 2026
DA - 2026/06/17
JO - The American Journal of Human Genetics
DO - 10.1016/j.ajhg.2026.05.010
UR - https://doi.org/10.1016/j.ajhg.2026.05.010
AB - Down syndrome, the most common form of human intellectual disability, results from nondisjunction and an extra copy of chromosome 21 (chr21), also known as trisomy 21 (T21). Small centromeres have been hypothesized to contribute to its etiology, and studies on mice suggest that larger centromeres are more efficiently transmitted, yet complete sequencing of chr21 centromeres has been particularly challenging due to their repetitive nature and homology to chromosome 13. Using long-read sequencing, we sequenced and assembled the centromeres from eight families with a child with T21 (one parent-child trio, six mother-child duos, and one singleton), all resulting from maternal meiosis I errors. A comparison of all proband chr21 centromeres (n = 24) to those of control individuals (n = 287) shows that small centromeres are not enriched in families with T21 (p value = 0.72), contrary to earlier reports. However, chr21 extreme centromere size asymmetry (>10-fold) was observed for two of them. Mothers from these two families with T21 carry some of the smallest chr21 centromeres (143 and 181 kbp) observed in female individuals to date, exhibiting a ∼10.7- and ∼19.4-fold centromeric α-satellite higher-order repeat array size difference between the maternally inherited homologs, respectively. Phylogenetic reconstruction reveals that human chr21 is particularly prone to such asymmetry, with some of the biggest size differences occurring over the last ∼17,000 years of human evolution.
SN - 0002-9297
SN - 1537-6605
ER -