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The region 21q22 is considered crucial for the pathogenesis of both Down syndrome (DS) and the partial monosomy 21q syndrome. Haploinsufficiency of the RUNX-1 gene, mapping at 21q22 is responsible for a platelet disorder and causes predisposition to myelodysplastic syndrome (MDS). We describe a 3-year-old girl with mental retardation, congenital he...
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Context 1
... studies from the peripheral blood and fibroblasts of the patient displayed a female karyotype with A partial deletion of chromosome 21: 46, XX, del(21)(q22.2q22.3) ( Fig. 2A). This result was further characterized and reinterpreted of the array CGH analysis (see below). Maternal and paternal karyotypes were ...
Context 2
... with chromosome 21 specific WCP-and centromere probes indicated that the derivative chromosome was composed entirely of material from chromosome 21 and that it contained two centromeric regions, not positioned at the ends but tandem of the structure (Fig. 2B). Hybridization with a NOR-specific probe RP5-1174A5 showed a signal at each end of the structure implying the presence of p-arm material in duplicate on the derivative chromosome (Fig. 2C). Hybridization with the LSI 21 and subtelomeric probes, specific for chromosome 21, showed signals only on the normal chromosome 21 homologue ...
Context 3
... was composed entirely of material from chromosome 21 and that it contained two centromeric regions, not positioned at the ends but tandem of the structure (Fig. 2B). Hybridization with a NOR-specific probe RP5-1174A5 showed a signal at each end of the structure implying the presence of p-arm material in duplicate on the derivative chromosome (Fig. 2C). Hybridization with the LSI 21 and subtelomeric probes, specific for chromosome 21, showed signals only on the normal chromosome 21 homologue implying a lack of these regions on the derivative chromosome. The control probe RP11-91n21, hybridizing to 21q11.2, was duplicated on the derivative chromosome, confirming the results of array ...
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We report a patient with speech delay and hydronephrosis ascertained with array-CGH screening of patients with abnormal neuronal migration and intellectual disability, having a 7q11.23 duplication reciprocal to the Williams-Beuren critical region (WBCR) deletion. Similarly to the reported patients, he showed serious difficulties in expressive langu...
Citations
... In our study, the rs35349742 SNP located in this gene exhibited a GWAS suggestive association to SC composite score, although gene analysis did not show any significant effect. This SNP maps at 21q22.12 region that has been associated to several neurodevelopmental disorders (Melis et al. 2011) and, in particular, pathogenic copy number variations (CNVs) located in this region have been found in ASD patients (Nevado et al. 2014;Mafalda et al. 2016;Chaves et al. 2019). Thus, it is possible to suggest, although this needs to be proved, that this gene may have a role in the SC deficits of people with SCZ through the modulation of other genes more directly connected to SC functioning. ...
Objectives
People with schizophrenia (SCZ) present serious and generalised deficits in social cognition (SC), which affect negatively patients’ functioning and treatment outcomes. The genetic background of SC has been investigated in disorders other than SCZ providing weak and sparse results. Thus, our aim was to explore possible genetic correlates of SC dysfunctions in SCZ patients with a genome-wide study (GWAS) approach.
Methods
We performed a GWAS meta-analysis of data coming from two cohorts made of 242 and 160 SCZ patients, respectively. SC was assessed with different tools in order to cover its different domains.
Results
We found GWAS significant association between the TMEM74 gene and the patients’ ability in social inference as assessed by The Awareness of Social Inference Test; this association was confirmed by both SNP-based analysis (lead SNP rs3019332 p-value = 5.24 × 10⁻⁹) and gene-based analysis (p-value = 1.09 × 10⁻⁷). Moreover, suggestive associations of other genes with different dimensions of SC were also found.
Conclusions
Our study shows for the first time GWAS significant or suggestive associations of some gene variants with SC domains in people with SCZ. These findings should stimulate further studies to characterise the genetic underpinning of SC dysfunctions in SCZ.
... This is not consistent with 6q+ in this case, so the correlation between 6q+ and secondary MDS still need more clinical studies. In addition, the patient's chromosome 21q− was associated with Down's syndrome, some complex diseases (familial compound hyperlipidemia, bipolar affective disorder), some single gene genetic disorders (amyotrophic lateral sclerosis, autoimmune polyadenopathy, Alzheimer's disease, etc.)[13], solid tumors (cervical cancer, lung cancer, breast cancer, etc.) and leukemia. Acute myeloid leukemia 1 (AML1) is located on the long arm of chromosome 21. ...
... [53] The RUNX1 gene (OMIM 151385) on chromosome 21q22.12 is a transcription factor that binds with promoters and enhancers in many genes. Runx1 copy number variation is associated with congenital heart malformation [54] including TOF [55] and thus differential methylation leading to aberrant expression of this gene in TOF is significantly plausible. ...
Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF.
... and distal deletions (from ∼ 36 to 37.5 Mb/telomere). Proximal 21q deletions result in a se-vere phenotype including craniofacial dysmorphism; skeletal, cardiac, and genital anomalies; severe intellectual disability, and a variety of hematological conditions [Lyle et al., 2009;Melis et al., 2011;Szabó et al., 2012]. Interstitial deletions are rare, probably attributed to a severe phenotype [Lyle et al., 2009]. ...
... Interstitial deletions are rare, probably attributed to a severe phenotype [Lyle et al., 2009]. In terminal 21q deletions, the phenotype is milder and includes hypertonia, hypothyroidism, facial dysmorphisms, a thin marfanoid build, mild intellectual disability with/without signs of holoprosencephaly or normal intelligence, and minor anomalies [Ahlbom et al., 1996;Lyle et al., 2009;Melis et al., 2011;Szabó et al., 2012;Wakui et al., 2002]. With the introduction of molecular methods for investigation, such as FISH, MLPA, and chromosomal microarray, a larger number of patients with these deletions are being identified. ...
Partial monosomy 21 results in a great variability of clinical features that may be associated with the size and location of the deletion. In this study, we report a 22-month-old girl who showed a 45,XX,add(12)(p13)dn,-21 karyotype. The final cytogenomic result was 45,XX,der(12)t(12;21)(p13;q22.11) dn,-21.arr[hg19] 21q11.2q22.11(14824453_33868129)×1 revealing a deletion from 21pter to 21q22.11. Clinical manifestation of the patient included hypertonia, a long philtrum, epicanthic folds, low-set ears, and café-au-lait macules - a phenotype considered as mild despite the relatively large size of the deletion compared to patients from the literature.
... Only a few cases of DS have been reported with partial trisomy overlapping the most telomeric part of human chromosome 21 [43,44] and so far none have been described with a trisomy limited to this segment. Conversely several cases with monosomy of the telomeric end have been described with mild phenotypes [45][46][47][48]. Similarly, analysis of trisomy and monosomy models for Cstb-Prmt2 showed no phenotypes in open field, in the Morris water Maze, either alone or in combination with the Tc1 transchromosome [15,29,49]. ...
Down syndrome (DS) results from one extra copy of human chromosome 21 and leads to several alterations including intellectual disabilities and locomotor defects. The transchromosomic Tc1 mouse model carrying an extra freely-segregating copy of human chromosome 21 was developed to better characterize the relation between genotype and phenotype in DS. The Tc1 mouse exhibits several locomotor and cognitive deficits related to DS. In this report we analyzed the contribution of the genetic dosage of 13 conserved mouse genes located between Abcg1 and U2af1, in the telomeric part of Hsa21. We used the Ms2Yah model carrying a deletion of the corresponding interval in the mouse genome to rescue gene dosage in the Tc1/Ms2Yah compound mice to determine how the different behavioral phenotypes are affected. We detected subtle changes with the Tc1/Ms2Yah mice performing better than the Tc1 individuals in the reversal paradigm of the Morris water maze. We also found that Tc1/Ms2Yah compound mutants performed better in the rotarod than the Tc1 mice. This data support the impact of genes from the Abcg1-U2af1 region as modifiers of Tc1-dependent memory and locomotor phenotypes. Our results emphasize the complex interactions between triplicated genes inducing DS features.
... Several cases of chromosomal aberration encompassing the Human chromosome 21q22.3 up to the qter regions have been reported (LYLE et al. 2009;HANNACHI et al. 2011;MELIS et al. 2011;ROBERSON et al. 2011) with mild phenotypes. In the ECARUCA database (www.ecaruca.net), ...
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.
... It is possible that fetuses with full monosomy 21 die before or soon after birth [Courtens et al., 1994;Huret et al., 1995;Oegema et al., 2010]. In contrast, at least 45 patients with partial deletion of chromosome 21 have been reported [Braddock and Carey, 1994;Courtens et al., 1994;Theodoropoulos et al., 1995;Chen et al., 2003;Yao et al., 2006;Hoyer et al., 2007;Beri-Dexheimer et al., 2008;Shinawi et al., 2008;Lyle et al., 2009;Fujita et al., 2010;Katzaki et al., 2010;Lindstrand et al., 2010;Oegema et al., 2010;Byrd et al., 2011;Click et al., 2011;Melis et al., 2011;Roberson et al., 2011;Thevenon et al., 2011;Izumi et al., 2012]. Among 21q22 microdeletion syndromes, Braddock-Carey syndrome with thrombocytopenia multiple anomalies and intellectual disability was first described in 1994 [Braddock and Carey, 1994]. ...
... This syndrome is caused by haploinsufficiency of RUNX1 [Katzaki et al., 2010;Braddock et al., 2011;Thevenon et al., 2011]. The clinical phenotypes of 21q22 deletion vary from normal to severe, depending on the size and position of the deletion [Courtens et al., 1994;Chettouh et al., 1995;Theodoropoulos et al., 1995;Yao et al., 2006;Beri-Dexheimer et al., 2008;Shinawi et al., 2008;Lyle et al., 2009;Fujita et al., 2010;Katzaki et al., 2010;Lindstrand et al., 2010;Melis et al., 2011;Roberson et al., 2011]. Moreover, three regions for partial monosomy 21 have been proposed based on genotype-phenotype correlation studies [Lyle et al., 2009;Roberson et al., 2011]. ...
... We present a Japanese patient with a de novo 1.4-Mb deletion at 21q22.11. To the best of our knowledge, at least 16 other reported patients share the deleted region and clinical manifestations with our patient (Table I) [Braddock and Carey, 1994;Orti et al., 1997;Albert, 2001;Yao et al., 2006;Hoyer et al., 2007;Beri-Dexheimer et al., 2008;Shinawi et al., 2008;Lyle et al., 2009;Katzaki et al., 2010;Lindstrand et al., 2010;Byrd et al., 2011;Click et al., 2011;Melis et al., 2011;Thevenon et al., 2011;Izumi et al., 2012]. Among the three described regions of partial monosomy 21, regions 2 and/or 1 may produce a more severe phenotype than that produced by region 3 [Lyle et al., 2009;van der Crabben et al., 2010;Roberson et al., 2011]. ...
Monosomy 21 is a very rare chromosomal abnormality. At least 45 patients with partial deletion involving 21q11 have been reported. Here, we report a Japanese boy who presented with pre- and postnatal growth delays, psychomotor developmental delay, microcephaly, and iris coloboma. Cytogenetic analysis revealed a de novo 1.4-Mb deletion at 21q22.11 containing 19 protein-coding RefSeq genes. We compared the clinical phenotypes between the present patient and 16 previously reported patients with a deleted region associated with postnatal growth delay and psychomotor developmental delay. Interestingly, ITSN1 was the only gene deleted or disrupted in all cases; this gene is known to be associated with intellectual disability. Microcephaly and brain structural abnormalities including polymicrogyria and agenesis/hypoplasia of the corpus callosum may also result from haploinsufficiency of ITSN1, highlighting its clinical significance for the neurological features of patients with monosomy 21. © 2014 Wiley Periodicals, Inc.
... In addition, we consider the deletion of RUNX1 gene a full explanation for the platelet disorder, in agreement with several papers (Melis et al., 2011;Michaud et al., 2002). RUNX1 is a transcription factor upregulated in megakaryocytes and down-regulated in erythroid cells; it plays a key role in the regulation of hematopoiesis, megakariocytopoiesis and leukemogenesis (Sroczynska et al., 2009). ...
The TGF-β signaling pathway controls cellular proliferation, growth and differentiation and regulates several functions of the connective tissue. Disruption of genes coding for components of the TGF-β signaling pathway or its interactors, such as fibrillin-1, has been showed to cause several human pathologies. Large deletions and non-sense mutations in TGFB2 gene have been recently described in patients with aortic aneurysm, scoliosis, arachnodactyly, chest deformities, joint hyper-flexibility, mild intellectual disability; this condition has been called Loeys-Dietz syndrome, type 4. In this paper we describe an 18-year-old girl with borderline mental impairment, seizures, retinal degeneration, short stature, congenital hip dysplasia, severe and worsening joint hypermobility, scoliosis, progressive deformation of the long bones, aortic dilatation and platelet disorder. Molecular study of DNA by CGH-Array demonstrated four de novo microdeletions: TGFB2 is among the genes deleted and we consider it the obvious candidate for the clinical phenotype. The multiple chromosomal rearrangements detected in the current patient can be ascribed to an event of constitutional chromothripsis.
... On the other hand, subjects with nearly absent ID and partial trisomy 21 might offer complementary clues to critical regions. It is important to critically evaluate all described cases and to continue searching for partial trisomy proposing molecular cytogenetics (CGH-Array) investigations (Melis et al. 2011) in particular in cases with a discordant genotype-phenotype relationship. Interesting advancements could also come by alterations (Table 1). ...
... 9,21 8,10,27,28 According to free-access medical and genetic literature databases (i.e., PubMed, database of genomic variants), subtelomeric rearrangements are associated or are the cause of intellectual disability, 21,29 intellectual disability of varying severity, seizures and congenital abnormalities, 30,31 moderate to severe learning difficulties, 32 and alterations in the central nervous system. [33][34][35] The clinical features of patient number 3 resembled those of the Birk Barel syndrome. 36 The identification of subtelomeric rearrangements as the genetic cause of intellectual disability is highly useful for geneticists, pediatric neurologists, and developmental pediatricians because it allows adequate medical care, genetic assistance, therapeutic focus, and prognosis. ...
