The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies

Abstract

Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-ofthe-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8 -16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease. copy number variants ͉ genomic structural variation ͉ human genome ͉ congenital heart disease ͉ leukemia F or over two decades trisomy 21 has represented a prototype disorder for the study of human aneuploidy and copy-number variation (1, 2), but the genes responsible for most Down syndrome (DS) phenotypes are still unknown. The analysis of several overlapping segmental trisomies 21 has led to the suggestion that dosage alteration through duplication of an extended region on chromosome 21 (HSA21) is associated with DS features (2-5, 42). However, humans with segmental trisomy 21 are rare, and thus humanbased DS-phenotypic maps have been of low resolution, far beyond the level of few or single genes, or even exons. Consequently, gene-disease links have often been based on indirect evidence from cellular or animal models (6, 7). Moreover, current hypotheses argue for the existence of a critical region, the DS consensus region (DSCR), responsible for most severe DS features (6, 8, 9), or presume the causative role of a small set of genes including DSCR1 and DYRK1A, or APP, for these phenotypes (6, 7).By using state-of-the-art genomics together with a large panel of partially trisomic individuals, we present the highest resolution DS phenotype map to date and identify distinct genomic regions that likely contribute to the manifestation of 8 DS features. Four of these phenotypes have never been associated with a particular region of HSA21. The map also enables us to rule out the necessary contribution of other HSA21 regions, thus pr...

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

“…Interestingly a high resolution analysis of human segmental trisomies suggests that more than one mental retardation critical region of HSA21 exists (62). Thus, many different triplicated genes are likely to contribute to the brain and behavioral phenotype in DS.…”

Down Syndrome: From Understanding the Neurobiology to Therapy

“…This neglect has been attributed in part to the presumed global nature of the molecular and cellular abnormalities resulting from trisomy 21 (T21), which involves misexpression of hundreds of genes in every cell throughout life. Several "dosage-sensitive" regions, including genes and noncoding conserved elements, have been mapped across the length of Hsa21 and shown to be sufficient for induction of the complete phenotype of DS (Korbel et al, 2009;Lyle et al, 2009). Exciting new findings are demonstrating the considerable plasticity of the human genome, and, in addition to direct and indirect alteration of expression of Hsa21 and nonHsa21 genes, we have to consider that the variability of the DS phenotype may also be a result of copy number alteration of functional, nontraditional genomic elements.…”

Trisomie 21 : 50 ans entre médecine et science

“…L'hypothèse de gènes individuels sensibles à l'effet-dose, qui est à la base de la notion de DSCR, n'est pas vérifiée par ce modèle murin, qui plaide plutôt pour un modèle d'interactions multiples. L'affinement des corrélations génotype-phénotype à partir de cas de trisomie 21 partielle par les techniques les plus récentes d'analyse du génome [39,40] montre que, bien que la majorité des signes cliniques puissent être rattachés à la région située entre 34 et 41 Mb, qui est la région du chr 21 la plus riche en gènes, d'autres régions sont importantes pour l'expression de certains aspects du syndrome. Au total, deux hypothèses, qui ne sont d'ailleurs pas mutuellement exclusives, coexistent pour expliquer les manifestations cliniques associées à la trisomie 21.…”