Genomic analysis of partial 21q monosomies with variable phenotypes

Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 02/2011; 19(2):235-8. DOI: 10.1038/ejhg.2010.150
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Partial monosomy 21 was recently segregated into three regions associated with variable clinical severity. We describe 10 new patients, all examined by single nucleotide polymorphism (SNP) genotyping and G-banded karyotyping. Cohort A consisted of three patients seen in our medical genetics clinics with partial chromosome 21 monosomies. In two of these patients having terminal deletions (21q22.2-ter and 21q22.3-ter), the breakpoints differed by at least 812 Kb of sequence, containing seven RefSeq genes. A third patient had an interstitial hemizygous loss of 16.4 Mb (21q21.1-q22.11). All three patients had relatively mild phenotypes. Cohort B consisted of seven patients with partial chromosome 21 monosomies who had a greater number of dysmorphic features and some major malformations; SNP genotypes were obtained from the Coriell Genetic Cell Repository. We also collected data on partial monsomy 21 cases from the DECIPHER database. This report of 10 new cases of 21q deletion and review of a total of 36 confirms that deletion of the terminal region is associated with a mild phenotype, but suggests that deletion of regions 1 and 2 is compatible with life and have a variable phenotype perhaps relating more to other genetic and environmental variables than to genes in the interval.

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    • "The analysis pinpointed a 5.3-Mb region from APP to SOD1 that is involved in intellectual disability, hypotonia and cranio-facial malformations. However, high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving Hsa21 do not indicate that a single region is crucial; instead, they reveal susceptible regions for the different phenotypes of PM21 (Lindstrand et al., 2010; Lyle et al., 2009; Roberson et al., 2011). "
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    ABSTRACT: Partial monosomy 21 (PM21) is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21). The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage-sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf). Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21. © 2015. Published by The Company of Biologists Ltd.
    Disease Models and Mechanisms 06/2015; 8(6):623-634. DOI:10.1242/dmm.017814 · 4.97 Impact Factor
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    • "With this new report, the Abcg1‐U2af1 region should be considered as an important genetic interval, containing key dosage sensitive elements controlling neurological phenotypes. The Ms2Yah mice should be further explored as a model of Hsa21 terminal deletion for which little consequence have been described so far (LYLE et al. 2009; LINDSTRAND et al. 2010; ROBERSON et al. 2011). On the opposite, increase in the Abcg1‐U2af1 region dosage may be determinant for the social behavior observed in Down syndrome. "
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    ABSTRACT: Down syndrome (DS) is due to increased copy number of human chromosome 21. The contribution of different genetic regions has been tested using mouse models. As shown previously, the Abcg1-U2af1 genetic region contributes to cognitive defects in working and short-term recognition memory in Down syndrome mouse models. Here we analyzed the impact of monosomy of the same genetic interval using a new mouse model, named Ms2Yah. We used several cognitive paradigms, and did not detect defects in the object recognition nor the Morris water maze tests. However, surprisingly, Ms2Yah mice displayed increased associative memory in a pure contextual fear conditioning test, and decreased social novelty interaction along with a larger long term potentiation recorded in the CA1 area following stimulation of Schaffer collaterals. Whole genome expression studies carried out on hippocampus showed that only the transcription of a small number of genes is affected, mainly from the genetic interval (Cbs, Rsph1, Wdr4), with a few additional ones, including the postsynaptic Gabrr2, Gabbr1, Grid2p, Park2 and Dlg1 and the components of the Ubiquitin mediated proteolysis (Anapc1, Rnf7, Huwe1, Park2). The Abcg1-U2af1 region is undeniably encompassing dosage sensitive genes or elements whose change in copy number directly impact learning and memory, synaptic function and autistic related behavior.
    Genetics 04/2014; 197(3). DOI:10.1534/genetics.114.165241 · 5.96 Impact Factor
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    • "Clinical phenotypes observed in patients with partial monosomies of chromosome 21 are very heterogeneous. Some patients show only mild to moderate intellectual disability, and have no other apparent dysmorphic or congenital malformations [3], [4], while others are diagnosed with a variety of severe clinical symptoms, such as profound intellectual disability, microcephaly, epilepsy, craniofacial, skeletal, cardiac and/or renal abnormalities and/or respiratory difficulties [5], [6], [7], [8], [9]. "
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    ABSTRACT: Haploinsufficiency of part of human chromosome 21 results in a rare condition known as Monosomy 21. This disease displays a variety of clinical phenotypes, including intellectual disability, craniofacial dysmorphology, skeletal and cardiac abnormalities, and respiratory complications. To search for dosage-sensitive genes involved in this disorder, we used chromosome engineering to generate a mouse model carrying a deletion of the Lipi-Usp25 interval, syntenic with 21q11.2-q21.1 in humans. Haploinsufficiency for the 6 genes in this interval resulted in no gross morphological defects and behavioral analysis performed using an open field test, a test of anxiety, and tests for social interaction were normal in monosomic mice. Monosomic mice did, however, display impaired memory retention compared to control animals. Moreover, when fed a high-fat diet (HFD) monosomic mice exhibited a significant increase in fat mass/fat percentage estimate compared with controls, severe fatty changes in their livers, and thickened subcutaneous fat. Thus, genes within the Lipi-Usp25 interval may participate in memory retention and in the regulation of fat deposition.
    PLoS ONE 01/2012; 7(1):e29681. DOI:10.1371/journal.pone.0029681 · 3.23 Impact Factor
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