title: Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel.
abstract: Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, two of these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion.
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Eva
authors.initials: E
authors.lastname: Lana-Elola
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Sheona
authors.initials: S
authors.lastname: Watson-Scales
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Slender
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Dorota
authors.initials: D
authors.lastname: Gibbins
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Martineau
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Douglas
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Mohun
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Elizabeth Mc
authors.initials: EM
authors.lastname: Fisher
authors.affiliation: The Francis Crick Institute, London, United Kingdom.|Imperial College London, London, United Kingdom.
authors.forename: Victor Lj
authors.identifier: http://orcid.org/0000-0003-2439-0798
authors.initials: VL
authors.lastname: Tybulewicz
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000473:pathology*; D018628:Gene Dosage; D056426:Genetic Loci; D006330:Heart Defects, Congenital / Q000235:genetics*; D051379:Mice
keywords: Down syndrome; chromosome engineering; congenital heart defects; developmental biology; human biology; medicine; mouse; mouse genetics; stem cells