Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Lyle, Robert; Béna, Frédérique; Gagos, Sarantis; Gehrig, Corinne; Lopez, Gipsy; Schinzel, Albert; Lespinasse, James; Bottani, Armand; Dahoun, Sophie; Taine, Laurence; Doco‐Fenzy, Martine; Cornillet‐Lefèbvre, Pascale; Pelet, Anna; Lyonnet, Stanislas; Toutain, Annick; Colleaux, Laurence; Horst, Jürgen; Kennerknecht, Ingo; Wakamatsu, Nobuaki; Descartes, Maria; Franklin, Judith; Florentin-Arar, Lina; Kitsiou, Sofia; Yahya-Graison, Emilie Aït; Costantine, Maher; Sinet, Pierre-Marie; Delabar, Jean Maurice; Antonarakis, Stylianos E.

doi:10.1038/ejhg.2008.214

Cited by 253 publications

(314 citation statements)

References 46 publications

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“…In agreement with Lyle et al, 2 we also found hemizygous deletions in a third region, from B36-37.5 Mb to the telomere, to be the most common abnormality (two from Cohort A, four from Cohort B, eight from DECIPHER, seven from Lyle et al). Also in agreement with Lyle et al, the phenotypes were relatively mild.…”

Section: Discussionsupporting

confidence: 78%

Genomic analysis of partial 21q monosomies with variable phenotypes

et al. 2010

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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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Section: Discussionsupporting

confidence: 78%

Genomic analysis of partial 21q monosomies with variable phenotypes

et al. 2010

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“…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.…”

Section: Gene Expression and Trisomy 21mentioning

confidence: 99%

Down Syndrome: From Understanding the Neurobiology to Therapy

Gardiner¹,

Hérault

Lott³

et al. 2010

J. Neurosci.

124

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Down syndrome (DS) is the most common example of a neurogenetic aneuploid disorder leading to mental retardation. In most cases, DSresults from an extra copy of human chromosome 21 producing deregulated gene expression in brain that gives raise to subnormal intellectual functioning. Understanding the consequences of dosage imbalance attributable to trisomy 21 (T21) has accelerated because of recent advances in genome sequencing, comparative genome analysis, functional genome exploration, and the use of model organisms. This has led to new evidence-based therapeutic approaches to prevention or amelioration of T21 effects on brain structure and function (cognition) and has important implications for other areas of research on the neurogenomics of cognition and behavior. IntroductionTrisomy for human chromosome 21 (Hsa21) is the most frequent live-born aneuploidy and results in Down syndrome (DS). This is a well recognized syndrome with variable phenotypic expression. DS results in cognitive impairment, dysmorphic features, and a number of mostly nonspecific manifestations for which severity and frequency are highly variable among different individuals.In DS, deficits in learning, memory, and language lead to a general cognitive impairment, which is typically in the mild-tomoderate range. Morpho-syntax, verbal short-term memory, and explicit long-term memory are usually more impaired, whereas visual-spatial short-term memory, associative learning, and implicit long-term memory are better preserved (for review,

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“…The first from the centromere to 31.2 Mb contains 50 genes and produces severe phenotype [13]. The second from 31.2 to 36 Mb contain 80 genes but deletion is rare in this region indicating intolerance in monosomic state [13]. The third from 36-37.5 Mb to the telomere contain 130 genes and result into a milder phenotype [3,13].…”

Section: Discussionmentioning

confidence: 99%

“…Three broad regions are implicated to the phenotype of monosomy 21. The first from the centromere to 31.2 Mb contains 50 genes and produces severe phenotype [13]. The second from 31.2 to 36 Mb contain 80 genes but deletion is rare in this region indicating intolerance in monosomic state [13].…”

Section: Discussionmentioning

confidence: 99%

“…The second from 31.2 to 36 Mb contain 80 genes but deletion is rare in this region indicating intolerance in monosomic state [13]. The third from 36-37.5 Mb to the telomere contain 130 genes and result into a milder phenotype [3,13]. The deletion in our patient spans from 36,854 to 46,006 Mb, downstream from the intolerant deletion region, but have more sever phenotype than that reported by Lyle et al Similar deleted segment, albeit smaller, was reported by Valetto et al [4] from position (37,713,441) (q22.13) to position 42,665,162 (q22.3) in a patient with dysmorphic features, intellectual disability and epilepsy [4].…”

Section: Discussionmentioning

confidence: 99%

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Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

Hussein¹

2015

J Mol Biomark Diagn

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We report on a new case with developmental delay, dysmorphic features, holoprosencephaly that showed deletion in long arm of chromosome 21 (21q22.13-q22.3). The patient is a male 3 months old presented with frontonasal dysplasia, scoliosis, abnormal ears, VSD, hypospadias, undescended testis. MRI has shown holoprosencephaly and agenesis of corpus callosum. Array-comparative genomic hybridization using the Agilent 2×400 oligoarray showed an interstitial deletion in chr21q22.13-q22.3, (start-end: 36,854,967-46,006,008 bp) deletion size is 9 Mb (9,151,042 bp) and includes 75 genes (Data base of genomic variants, hg18). The deletion was found to be maternal in origin. The findings from this report underscore the role of the genes at chromosome 21q22.13-q22.3 in brain development and indicate the usefulness of array-CGH in identification of the deletion size and detection of genes that could be correlated to the patient's phenotype.

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Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Cited by 253 publications

References 46 publications

Genomic analysis of partial 21q monosomies with variable phenotypes

Genomic analysis of partial 21q monosomies with variable phenotypes

Down Syndrome: From Understanding the Neurobiology to Therapy

Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

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