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Conceived and designed the experiments: SG EEE. Performed the experiments: SG CB LV THV NS. Analyzed the data: SG. Contributed reagents/materials/analysis tools: SG EEE BPC ZB STW WHR CSM CR MF GBF MS RB. Wrote the paper: SG EEE.
While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p=9.58×10−11, odds ratio=4.59), dyslexia (p=3.81×10−18, odds ratio=14.45), or controls (p=2.75×10−17, odds ratio=13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p=2.4×10−6, odds ratio=6) or ID (16%, p=3.55×10−12, odds ratio=10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p=0.001, odds ratio=2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p=0.07, odds ratio=2.33).
Deletions and duplications, termed copy number variants (CNVs), have been implicated in a variety of neurodevelopmental disorders including intellectual disability (ID), autism, and schizophrenia. Our understanding of the relevance of large, rare CNVs in a range of neurodevelopmental phenotypes, varying in severity and prevalence, has been difficult because these studies were restricted to the analysis of one disorder at a time using different CNV detection platforms, insufficient sample sizes, and a lack of detailed clinical information. We tested 1,227 individuals with different neurological diseases including dyslexia, autism, and ID using the same CNV detection platform. We observed striking differences in CNV burden and inheritance characteristics among these cohorts and show that ID is the primary correlate of large CNV burden. This correlation is well illustrated by a comparison of autism patients with and without ID—where the latter show only modest increases in large CNV burden compared to controls. We also find significant depletion in the frequency of large CNVs in dyslexia compared to the other cohorts. Further studies on larger sets of individuals using high-resolution arrays and next-generation sequencing are warranted for a detailed understanding of the relative contribution of genetic variants to neurodevelopmental disorders.
Recent studies have implicated large, rare CNVs in a range of neurodevelopmental disorders including intellectual disability (ID) [1], [2], autism [3], [4], schizophrenia [5], [6], bipolar disorder [7], [8], epilepsy [9], [10], and attention deficit hyperactivity disorder (ADHD) [11], [12]. Several themes have emerged from these studies: first, a significant enrichment for rare CNVs in individuals with the disease compared to unaffected controls was observed, independently, for each of these disorders; second, the same recurrent CNVs are associated with different neuropsychiatric phenotypes; and third, locus heterogeneity is substantial as many distinct variants can lead to similar phenotypes.
Our understanding of the relevance of rare CNVs across a broad spectrum of neurodevelopmental disorders, varying in severity and prevalence, is limited as previous studies were restricted to the analysis of one phenotype at a time and each of such studies was performed using different CNV genotyping methodologies with distinct platform-specific biases, making comparisons difficult. We undertook a systematic analysis of 1,227 cases and 337 controls to assess the relative contribution of CNVs in three phenotypically distinct neurodevelopmental disorders. We designed a whole-genome custom microarray targeted to genomic hotspots for comparative genomic hybridization (CGH) to identify potentially pathogenic CNVs that contribute to ID, autism, and dyslexia.
We analyzed 1,227 individuals ascertained for three neurodevelopmental disorders: 376 dyslexic children with a verbal IQ (VIQ) ≥90 on the Wechsler Intelligence Scale for Children [13] and dyslexia defined as poor performance and IQ-performance discrepancy in one or more of a set of standardized reading measures, 350 cases with sporadic autism from the Simons Simplex Collection (SSC), and 501 cases with ID. We used 337 NIMH control individuals for comparison. Further, based on the presence or absence of ID (full-scale IQ score cutoff of 70), autism cases were divided into those with ID (n=97) or without ID (n=253) (see Materials and Methods). Based on the presence of multiple congenital anomalies (MCA), individuals with ID were divided into those with ID only—i.e. idiopathic ID (n=428)—and those with ID and MCA (n=73).
All copy number variation analyses were performed using a custom microarray with a high probe density (~2.6 kbp) targeted to 107 genomic hotspot regions [14] (~251 Mbp) and a median probe spacing of ~36 kbp in the genomic backbone (see Materials and Methods, Table S1). We used a Hidden Markov Model (HMM)-based algorithm to identify deletions and duplications. We restricted our analysis to CNVs >50 kbp in size to reduce false positive calls and validated all relevant CNVs using a second custom designed high-density array. To empirically determine the validation rate of the array at different genomic regions, we examined 118 CNVs detected in 24 samples and confirmed 117 events (>99% accuracy, see Table S2). While we were easily able to detect smaller events in the hotspot regions, the specificity of the array restricted our CNV discovery to >50 kbp in hotspot-associated regions and to >300 kbp in regions not associated with genomic hotspots (Figure S1).
After quality control (QC) filtering and manual curation, we obtained 5,086 CNVs in 1,395 out of 1,564 individuals (89.2%) with high-quality array CGH data (Table 1; Datasets S1, S2, S3, S4). Using these data, we compared the CNV enrichment between the multiple cohorts tested. We found a significant excess of large CNVs (>1 Mbp) in individuals with ID (p=2.75×10−17, odds ratio=13.71) or autism (p=0.012, odds ratio=2.99) when compared to controls analyzed on the same microarray platform (Figure 1). The frequency of large CNVs among children with dyslexia was similar to controls (p=0.64, odds ratio=0.94), although this might indicate a lack of statistical power in our study to detect any subtle enrichment (power >0.8 to detect 4.2% increase in burden) for large CNVs in dyslexia.
Within the neurodevelopmental disorder cohorts, a comparison showed a significantly greater large CNV burden in individuals with ID compared to autism (p=9.58×10−11, odds ratio=4.58) or dyslexia (p=3.81×10−18, odds ratio=14.45). When we partitioned the ID cohort into subsets with and without MCA, we observed a significantly increased large CNV burden in individuals with ID/MCA compared to ID alone (p=0.001, odds ratio=2.54). This trend was also observed when individuals with autism were separated into those with ID and without ID (Figure 1), although not statistically significant (p=0.102, odds ratio=2.1). When compared to controls, we noted a trend for increase in large CNV burden for autism without ID (p=0.07, odds ratio=2.33) as well as autism with ID (p=0.0048, odds ratio=4.85). In addition, a gene-based analysis showed an incremental increase in the proportion of disrupted genes and average gene density per CNV with higher estimates for the ID/MCA cohort as compared to ID alone or autism (Table 1). We also note that within the cohorts no bias towards deletions or duplications was observed in relation to phenotypic severity or variability (Tables S3, S4, S5, S6, S7). Overall, our results suggest a positive correlation of the severity of the phenotype to the size and gene density of CNVs.
To identify rare CNVs of likely pathogenic significance, we compared the pattern of CNVs from dyslexia, autism, ID, and NIMH control cohorts to a map developed from an expanded set of 8,329 normal individuals genotyped with Illumina microarrays and to the publicly available Database of Genomic Variants [15] (see Materials and Methods). We eliminated common copy number polymorphisms and CNVs from our cases if they had a reciprocal overlap of 50% or more of their length with CNVs found in these 8,329 controls. After filtering, we compared the groups. We found a significant increase of rare CNVs in individuals with autism (35/336, 10%; p=2.4×10−6, odds ratio=6) or ID (69/431, 16%; p=3.55×10−12, odds ratio=10) compared to individuals with dyslexia (6/322, 2%) (Figure 2A, Table 2). In fact, when analyzed separately, the frequency of rare CNVs in NIMH controls (6/306, 2%) was not different compared to dyslexia (p=0.57, odds ratio=0.94) (Table S8).
Given the high population prevalence of dyslexia [16], we then relaxed our selection to include events present at an allele frequency of <0.1% in controls (8/8,635) and identified four additional CNVs—i.e., a total of 10 CNV events (Table 3). The analysis of hotspot regions identified only one individual with dyslexia who carried a 15q11.2 BP1–BP2 deletion, which has previously been associated with ID [17], schizophrenia [18], [19], and epilepsy [20]; however, this deletion was also observed in 25/8,635 of our total control individuals. None of the seven deletions and three duplications detected in our dyslexia cohort mapped to candidate loci known to be associated with dyslexia [21].
Analysis of 336 individuals from the SSC autism cohort showed that 35 individuals (10%) carried 36 rare CNVs (680 RefSeq genes, median size=662 kbp) and about 58% (21/36) of these CNVs mapped to genomic hotspots (Table 2). Only eight of the events (all hotspot sites) associated with genomic disorders, including 22q11.2 deletion (TBX1, DiGeorge syndrome), 17p12 duplication (PMP22, Charcot-Marie-Tooth disease), and 15q11.2q13.1 duplication (UBE3A and SNRPN) (Table S9). In addition, as reported previously [3], [22], [23], the autism-associated proximal 16p11.2 deletion (TBX6) was observed in approximately 1% (3/336) of all autism cases analyzed. Interestingly, one case with a de novo 16p11.2 deletion also inherited a 2 Mbp duplication 22q11.2 (TBX1) from the mother.
Among 431 cases with ID (358 cases with ID only and 73 cases with ID plus MCA), 69 individuals carried 77 rare CNVs (2,215 RefSeq genes, median size=1.5 Mbp) that were either of known pathogenic significance or not observed in a total set of 8,635 controls, and 32% (25/77, median size=1.42 Mbp) of these variants localized to genomic hotspot regions (Table 2). This is a significant enrichment for rare CNVs in the ID cohort compared to autism (p=0.019, odds ratio=1.6) or dyslexia cohorts (p=3.55×10−12, odds ratio=10). Interestingly, 20/77 CNVs (16 hotspot and four non-hotspot sites) mapped to a known genomic disorder site, including those associated with variable phenotypes such as 15q13.1q13.3 (CHRNA7), 16p11.2 proximal (TBX6; two cases) and distal (SH2B1) hotspots, 16p13.11 (MYH11; three cases), 17q12 (TCF2), and 3q29 (DLG1) as well as syndromic regions such as 7q11.23 (Williams syndrome), 17q21.31 (MAPT), 5q35 (Sotos syndrome), 8p23.1, 22q13 (Phelan-McDermid syndrome) [24] and 1p36 [25].
We next sought to determine whether these rare CNVs were inherited or if they arose de novo in the probands. Parental DNA samples were available to investigate inheritance for 90 out of 123 rare CNVs detected in all three disease cohorts (Table S8). In four cases, only maternal DNA was available. We find that 44/90 CNVs arose de novo and a majority (77%, 34/44) of these de novo CNVs were large (>1 Mbp). Overall, we find a greater proportion of de novo events in ID (64%, 30/47) compared to autism (40%, 14/35; p=0.027, odds ratio=2.6) or dyslexia (0/8; p=0.0009, odds ratio=infinity) (Figure 2B). These data are suggestive of a general trend of increased de novo rates and CNV size with increased severity of the disorder.
We then focused on rare CNVs involving single genes or regions of potential interest. In the dyslexia cohort, two unrelated families carried CNVs on chromosome 7q11.23 that involved the autism susceptibility candidate 2 (AUTS2, MIM# 607270). A 669 kbp duplication that included AUTS2 and WBSCR17 was transmitted from an affected father to the daughter and an approximately 84 kbp deletion was transmitted from the affected paternal grandmother through the unaffected father to the proband (Figure 3). In addition, we also identified a 354 kbp deletion encompassing AUTS2 in one individual with idiopathic ID, pervasive developmental delay, partial epilepsy, and left hemihypertrophy. An approximately 1.2 Mbp deletion encompassing the eyes shut drosophila homolog gene (EYS, MIM# 612424) on chromosome 6q12 was detected in an affected proband and several unaffected family members. Although autosomal recessive single-nucleotide mutations in EYS have been reported in patients with retinitis pigmentosa [26], [27], the role of heterozygous microdeletions involving this gene is unknown.
We also identified a 471 kbp deletion involving IMMP2L inherited by the proband from the affected mother (Figure 3). Deletions involving IMMP2L have been associated with ADHD [12], autism [28], and Tourette syndrome [29]. Recently, Pagnamenta and colleagues also reported a 594 kbp IMMP2L-DOCK4 deletion resulting in a fusion transcript and an intragenic DOCK4 deletion segregating with dyslexia [30]. Our results are best interpreted within the context of candidate gene identification in dyslexia. Although at least nine chromosomal loci are associated with dyslexia, for two of these loci the candidate genes were identified on the basis of a rare balanced chromosomal translocations disrupting ROBO1 [31] and DYX1C1/EKN1 [32], [33]. More recently, a Danish Cytogenetic Registry study of all cases with chromosomal translocations identified additional novel dyslexia candidate genes affirming the value of rare structural variants in understanding the genetics of dyslexia [34]. Our study is the first to systematically characterize rare CNVs in dyslexia and thus evaluate the contribution of rare deletions and duplications to this common genetic disorder.
Within the autism cohort, several novel deletions and duplications involving neurologically-relevant genes were identified. A 5 Mbp de novo deletion involving FOXP1 on chromosome 3p14.1 was identified in an individual with features of idiopathic autism (full-scale IQ=75). An additional 6.6 Mbp de novo deletion overlapping FOXP1 was also identified in an individual with idiopathic ID (Figure 4). A review of the DECIPHER database revealed a similar-sized deletion disrupting FOXP1 in an individual with developmental delay, sensorineural deafness, hypotonia, club foot, and dislocation of hip. Recently, FOXP1 was implicated in autism, ID, and language impairment [35], [36], [37]. It is believed that FOXP1interacts with FOXP2 and CNTNAP2, both implicated in speech disorders and autism [38], [39]. The overlapping 1.16 Mbp region of the deletion common to both autism and ID indicates a potential involvement of FOXP1 in pathways related to both of these disorders. Other variants involving functionally relevant genes include 7q36.2 deletion and duplication (DPP6), 17q23.3 duplication (SCN4A), and 17q21.32 duplication (WNT3 and WNT9B).
Our analysis of the ID cohort was enriched for singleton events often involving genes related to developmental or neurological functions including SYNPR, GABRA, AUTS2, FOXP1, FKBP6, COBL, and FMR1. However, within the same cohort we were also able to detect novel overlapping deletions (3.5 Mbp and 9 Mbp) on chromosome 9p24 in two unrelated individuals (Figure 5A). Both cases exhibited clinical features of ID and Pervasive Developmental Delay-Not Otherwise Specified. The distal breakpoints of these deletions map to segmental duplications while the proximal end maps within a high density of repeat elements. A survey of this region in the DECIPHER database [40] revealed about 15 cases with overlapping deletions. Variable clinical presentations and heterogeneity of deletion breakpoints preclude further genotype-phenotype correlation studies for this region (Figure S2). We also identified a nonrecurrent 6q16 deletion (chr6: 100,383,567-103,310,184) that potentially narrows the critical region for this recently described Prader-Willi-like syndrome [41] to approximately 2.9 Mbp. The refined critical region contains only five genes including the obesity-associated SIM1 [42] and the autism-associated GRIK2 [43] (Figure 5B). About 70% of children with 6q16 deletion manifest obesity [41]; however, our case with the smaller deletion, encompassing SIM1, showed no evidence of obesity at 10 years of age (Table S10).
We find that 8/69 (11.6%) cases in the ID cohort carried more than one large, rare CNV and all of these individuals presented with severe clinical features (Tables S6, S7, S8). A striking difference (p=0.008, odds ratio=11.2) in multiple CNV rates was also observed when the ID cohort was divided into those with severe MCA (44%) and those with idiopathic ID (6.7%). Notable examples are co-occurrences of a 3.4 Mbp 16p13.11 duplication and a 3.3 Mbp deletion on chromosome 4q25 involving PITX2 in a case with features of Rieger syndrome [44] (Figure 6) and a 17p13.3 deletion (YWHAE, Miller-Dieker syndrome) and 3q29 duplication (DLG1) in a child with cryptorchidism, ventricular septal defect, and seizures. The 3q29 duplication is a recurrent interstitial rearrangement [45], [46] potentially mediated by flanking segmental duplications of high sequence identity (27 kbp size, 96% identity). The 17p13.3 deletion is a previously reported nonrecurrent rearrangement associated with Miller-Dieker syndrome [47], [48]. In contrast, only 1/35 (2.9%) autism cases and none of dyslexia individuals carried another large CNV. This observation suggests that the severity of the phenotypes can be influenced by more than one large, rare CNV co-occurring in the same individual. During this analysis we considered the possibility of a derivative chromosome representing an unbalanced translocation possibly creating the impression of multiple CNVs in our cases. We carefully reviewed available chromosomal analysis data (G-banded karyotyping or FISH) for each of the individuals with two hits reported in our study. We did find one case with two hits where apparent CNVs represent a derivative chromosome inherited from a balanced translocation carrier parent (Table S8D).
Initial discoveries of significant enrichment of rare CNVs for ID and autism led to testing the CNV basis for other behavioral and neurodevelopmental disorders of varying population frequency and severity, such as schizophrenia, ADHD, epilepsy, bipolar disorder, and Tourette syndrome. However, comparisons between these studies have been difficult due to differences in study design, insufficient sample sizes, and lack of detailed phenotype information. In this study, we compared 1,564 individuals (cases and controls) on a single platform of relatively modest density with the same type of detection bias. We utilized the duplication architecture of the human genome to custom design a DNA oligonucleotide microarray enriched for genomic hotspots, i.e., regions flanked by high-identity segmental duplications. This array has an advantage over several other commercial arrays in that there is a 25-fold enrichment for recurrent events in the genomic hotspots compared to the rest of the genome [49]. Therefore, fewer samples are required to identify several unrelated individuals with the same pathogenic mutation. We find that our array has a comparable diagnostic yield of 16% for the ID cohort compared to other clinical chromosomal microarray studies reported in the literature (Figure S3).
In strong agreement with previous studies, our data suggest that multiple, rare CNVs contribute to the etiology of autism and ID. In contrast, we find no increase in large pathogenic CNVs in individuals with dyslexia compared to controls. Notwithstanding, our analysis revealed novel regions of potential relevance to the etiology of dyslexia. Two unrelated children (2/322, 0.6%) with dyslexia carried CNVs encompassing AUTS2, both inherited from a parent. While the phenotype of dyslexia segregated with the AUTS2 duplication in the first family (Figure 3A), in the second family the deletion was inherited from affected grandmother through unaffected father (Figure 3B). This could be due to a phenomenon described as "compensation", where some adults that reported difficulties with reading in childhood no longer evidence signs of dyslexia [50]. Previous studies of de novo chromosomal translocations and inversions identified breakpoints within AUTS2 in individuals with autism and/or ID phenotypes [51], [52], [53], [54], [55]. More recently, unique AUTS2 deletions and duplications were observed in Juvenile Myoclonic Epilepsy [10] and ADHD [11], [12]. It is interesting to note that ADHD and dyslexia are frequently comorbid and may have shared genetic risk factors [56], [57], [58]. When our study is taken together with recent CNV studies of ADHD [11], [12], AUTS2 CNVs were observed in 5/2,306 combined cases and 3/46,947 unscreened controls (p=1.12×10−5, odds ratio=33.9), indicating that AUTS2 might have an important role in pathways related to cognition. While the function of AUTS2 is still unclear, it is strongly expressed in fetal and adult brains, particularly in the frontal, parietal, and temporal lobes [59]. Interestingly, AUTS2 and the 7q11.2 region were identified as having the strongest statistical signal for positive selection in early modern humans as compared to the Neanderthal genome [60], indicating that AUTS2 might be important for a specialized human function such as cognition.
The CNV profile we observed in individuals with dyslexia was essentially the same as that in control individuals. This is not surprising if we take into consideration that all the subjects in our dyslexia sample had a VIQ above the 25%ile and the mean VIQ of the cohort was 110 (2/3 standard deviations above the general population mean), and given that we have shown that the CNV profile correlates with the severity of ID. The genes involved in dyslexia are likely to affect more specialized cognitive functions, may not adversely affect general intelligence, and may be more amenable to discovery with high-density arrays capable of detecting single gene or single exon CNVs or SNP microarrays that can leverage SNP allele frequency information in addition to signal intensity. In addition, all hybridization-based platforms fail to detect copy number neutral changes, such as balanced chromosomal rearrangements and inversions. This is particularly germane to dyslexia where a large number of candidate genes have been identified through mapping of translocation breakpoints [21], [34].
A comparison of rare de novo CNV rates for autism shows that our estimates (4%, 14/336) fall within a range of 4–10% reported previously by other large-scale, high-density array studies [4], [61], [62], [63]. This suggests that no platform-specific bias exists for large variants and also that the contribution of large CNVs is consistent across all studies for autism. We find a significantly greater enrichment for large CNVs, higher de novo rates, and a higher frequency of two rare CNV hits in individuals with ID-associated phenotypes compared to autism or dyslexia. This observation is exemplified by the fact that individuals with autism with ID have more large CNVs than those with autism only. We also find a significant difference between individuals with autism versus those with dyslexia. Sanders and colleagues recently analyzed 1,124 SSC families affected with autism spectrum disorder (ASD). Using stepwise linear models, they evaluated the relationship between intellectual functioning, sex, and the number of genes within rare, de novo CNVs. While the number of genes affected correlated with the size of the de novo CNV, the authors did not find a strong correlation of the Autism Diagnostic Observation Schedule (ADOS) combined severity score (p=0.25, R2=0.005) or full-scale IQ (p=0.02, R2=0.08) with the size of the CNV. In contrast, we considered all large CNVs (common and rare, de novo and transmitted) identified in a relatively smaller sample size and essentially bifurcated the autism cohort using a full-scale IQ score cutoff of 70. There was also a greater enrichment of two hits in the ID cohort (11.6%) compared to the autism cohort (2.8%). In fact, one individual carrying a 16p11.2 deletion with autism and features of ID also has a maternally inherited 22q11.2 duplication (TBX1) providing further evidence for the two-hit hypothesis we previously proposed for severe developmental delay [64]. Further, the frequency of two hits was even more striking when only individuals with ID/MCA were considered (44%), albeit the number of cases is few. We believe these data provide support for an incremental effect of CNV size and number on the severity of phenotypic outcome.
Our experimental design is biased towards interrogating hotspot regions in the human genome. A comparison to recently reported studies [61], [63] suggests that the majority of false-negative calls will reside within non-hotspot regions due to a lack of probe coverage (<10 probes). While the detection power of our array increases with the size of the variant, we would certainly miss smaller and intragenic CNVs, for example in autism candidate genes such as NRXN1 [65], [66], CACNA1C, SLC4A10, MAGI1 [63], SYNGAP1, DLGAP2 [62], NLGN1, ASTN2 [67], and exonic copy number variants in ASPM, DPP10, CNTNAP2, A2BP1, PCDH9 [68], and PTCHD1 [69]. While we find no excess of large CNVs in dyslexia, there is still the possibility that large CNVs are relevant in some familial cases of the disease as well as occasional sporadic cases. Further studies are warranted for a more detailed analysis of all the three neurodevelopmental cohorts using high-resolution arrays and next-generation exome and/or whole-genome sequencing. While it can be difficult to compare data derived from different microarrays, there is value to multiple array platforms and cross-platform validation. The depositing of the resulting data into publicly available databases will facilitate the continued elucidation of recurring clinically significant CNV and genotype-phenotype correlations.
Patients from each of study cohort were recruited after appropriate human subjects approval and informed consent. Informed consent was also obtained to publish photographs.
DNA samples were obtained from cases ascertained for three neurodevelopmental disorders of varying severity: (1) ID/developmental delay and MCA, (2) dyslexia or reading impairment, and (3) idiopathic autism. We defined severity of clinical features based on presence or absence of ID (IQ<70) for the autism group and congenital malformation for the ID group. Our dyslexia cohort had no ID or congenital malformation cases; as an IQ≤90 and the presence of congenital malformations were exclusion criteria. Individuals with idiopathic autism were partitioned into those with autism and ID (IQ<70) and those without ID (IQ>70). For the ID cohort, those individuals with brain malformations, gross craniofacial dysmorphology, cardiac defects, and neurological deficits were separated into an ID plus MCA (ID/MCA) group. Thus, in the order of severity, the ID/MCA cohort is considered the most severe, followed by ID only, autism with ID, autism without ID, dyslexia, and normal controls. However, we note that although the individuals with dyslexia do not have ID, they have severe impairments in core phonological measures leading to significantly reduced reading abilities despite normal IQ (IQ≥90). Detailed descriptions of each of the cohorts are given below.
For the dyslexia subject set, children were considered eligible for the study if they met researcher-defined criteria based on test scores from a standardized battery of tests. DNA samples were obtained from two cohorts. The first cohort included probands aged 6 to 16 from 198 families who were initially ascertained at the University of Washington (UW) multidisciplinary Learning Disability Center (UWLDC) under protocols approved by the UW Institutional Review Board. For the UWLDC cohort, probands were required to have a prorated VIQ at or above 90 (≥25%ile) on the Wechsler Intelligence Scale for Children – 3rd edition [13], with performance below the age-specific population mean and at least one standard deviation below the VIQ on one or more out of 10 research measures of reading, writing, or spelling. As a group, on average, probands met the impairment criteria between 6 and 7 measures. As expected by ascertainment requirements, the average VIQ of probands in this cohort was 110 (≥75%ile) [70], [71]. Siblings older than 6.5 years were invited to participate, and additional family members were added using a sequential sampling strategy to extend pedigrees through family members with the most extreme impairment values on the same 10 research measures. Detailed recruitment and evaluation procedures for the UWLDC cohort were described earlier [50], [72] (see Table S4A).
For the second cohort, 178 children aged 5 to 12 were recruited from a special K-6 school for students with dyslexia or via their direct relatives in the Atlanta area (The Schenck School, Atlanta, GA). For this cohort, children were required to have a psychological battery of tests completed by a licensed psychologist and usually have a diagnosis of a reading disability. Based on strong verbal comprehension score, perceptual reasoning score, Peabody picture vocabulary test, or other cognitive tests that measure intelligence, these children have average to above-average intelligence. Both cohorts were composed of individuals with >90% Caucasian ethnicity with an approximately equal number of males and females. Except for ADHD, children with other psychiatric and neurological disorders, moderate to severe receptive language disorders, developmental disabilities, or other conditions known to affect cognition were excluded based on parental questionnaire. Clinical details are shown in Table S4B.
For the autism cohort, families were identified through the SSC (www.sfari.org) [73]. The Simons Foundation-funded SSC includes families with no more than one child with autism ascertained through 12 data collection sites across North America. Of the 350 individuals included in this study 297 (85%) are of Caucasian ethnicity. Inclusion criteria in the collection requires that the child with autism meet ASD criteria on the ADOS [74], on the Autism Diagnostic Interview, Revised (ADI-R) [75], and meet expert clinical judgment. Nonverbal IQ estimate must also be greater than 35. Children with significant hearing, vision, or motor problems, significant birth complications (e.g. extended NICU stay), or with a diagnosis of ASD-related disorders, such as Fragile X, were excluded. Children with a relative (up to third degree) with ASD or sibling who showed ASD-related symptoms were also excluded. Diagnostic evaluations, cognitive assessment, and phenotypic characterization were conducted at each site with data collection, data entry, and data validation methods standardized across sites to ensure reliability of sample collection. We further partitioned the autism cohort into those associated with ID (average full scale IQ=49) consisting of 97 cases (73 males, 24 females; median age, 12 years) and those without ID (average full scale IQ=98.9) comprising 253 cases (228 males, 25 females; median age, 11 years and 11 months). Clinical details are shown in Table S5.
The idiopathic ID cohort was selected from individuals admitted to the IRCCS Associazione Oasi Maria Santissima and screened for ID according to the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) criteria. This cohort consists of 428 cases (153 females, 275 males; median age, 15 years) of Caucasian ethnicity with idiopathic ID and previously excluded for common causes of ID, including Fragile X syndrome, trisomies 21 and 13. In addition, classical genomic syndromes such as Smith-Magenis, DiGeorge, Prader-Willi/Angelman, and Williams syndromes, if recognized by clinical evaluation, were followed up for confirmation using targeted multiplex ligation-dependent probe amplification and excluded. We note that cases with phenotypic variability that escape clinical detection might not have been excluded. Typically, idiopathic cases of ID with no classical constellation of clinical features suggestive of a known disorder or those with mild to moderate ID without significant congenital malformation were included in this cohort. Clinical details are shown in Table S6.
Individuals with features of ID with MCA not necessarily assigned to a specific syndrome were evaluated and recruited at the University of Torino. This cohort consists of 73 individuals (32 females and 41 males) of Caucasian ethnicity with a median age of 2 years at diagnosis. Clinical features of these individuals included brain malformations, craniofacial dysmorphology, and neurological deficits along with variable ID (Table S7). Informed consent was obtained from all the subjects included in both the studies.
The control cohort consisted of 337 DNA samples obtained from the Rutgers University Cell and DNA Repository (www.rucdr.org). These individuals were ascertained by the NIMH Genetics Initiative [76] through an online self-report based on the Composite International Diagnostic Instrument Short-Form (CIDI-SF) [77] and screened specifically for eight mental health disorders, including major depression, bipolar disorder, and psychosis, but were not screened for dyslexia and therefore not ideal for such comparisons. Those who did not meet DSM-IV criteria for major depression, denied a history of bipolar disorder or psychosis, and reported exclusively European origins were included [78], [79].
Additionally, CNV data from 8,329 additional cell line and blood-derived controls were used to assess the frequency of our putative pathogenic CNVs in a larger population of neurologically normal individuals. These data were derived primarily from genome-wide association studies of non-neurological phenotypes. Although these data were not ascertained specifically for neurological disorders, they consist of adult individuals providing informed consent. Specifically, datasets from the following sources were included in our analysis: Human Genome Diversity Project [49], [80]; National Institute of Neurological Disorders and Stroke (NINDS) (dbGaP accession no. phs000089) [49], [81]; Pharmacogenomics and Risk of Cardiovascular Disease (PARC/PARC2) [82], [83]; parents of asthmatic children courtesy of Stephanie London [49]; Fred Hutchinson Cancer Research Center (prerelease data provided courtesy of Aaron Aragaki, Charles Kooperberg, and Rebecca Jackson as part of an ongoing genome-wide association study to identify genetic components of hip fracture in the Women's Health Initiative); InCHIANTI (data provided by InCHIANTI study of aging, www.inchiantistudy.net) [49], [84]; and the Wellcome Trust Case Control Consortium phase 2 (National Blood Service) [7]. All samples were genotyped on Illumina arrays using methodology described previously [49] [85] and either natively processed in hg18 or re-mapped after CNV calling (NINDS and PARC) to hg18 using the UCSC LiftOver tool (http://genome.ucsc.edu).
We designed custom targeted hotspot v1.0 arrays comprised of 135,000 probes (by Roche NimbleGen) with higher density probe coverage (median probe spacing 2.6 kbp) in the genomic hotspots (regions flanked by segmental duplications) and a lower probe density in the genomic backbone (median probe spacing 36 kbp). All microarray hybridization experiments were performed as described previously [86], using a single unaffected male (GM15724 from Coriell) as reference. All validation experiments were performed using two custom array designs: (1) a custom targeted 4×180 K Agilent chip with median probe spacing of 2 kbp in the genomic hotspots and whole-genome backbone coverage of one probe every 36 kbp (Agilent Technologies) and (2) a custom targeted 3×720 K NimbleGen or 2×400 K Agilent chip with median probe spacing of 500 bp in the genomic hotspots and probe spacing of 14 kbp in the genomic backbone.
All arrays were analyzed by mapping probe coordinates to the human genome assembly Build 36 (hg18). Using chromosome-specific means and standard deviations, normalized log intensity ratios for each sample were transformed into z-scores. These z-scores were then classified as "increased", "normal", or "decreased" in copy number using a three-state HMM. The HMM was applied using HMMSeg [87]. For each sample, HMM state assignments of probes were merged into segments if consecutive probes of the same state less than 50 kbp apart. If two segments of the same state were separated by an intervening sequence of ≤5 probes and ≤10 kbp, both segments and intervening sequence were called as a single variant. Further, we employed stringent QC measures and empirically estimated post-HMM filtering thresholds (absolute z-score >1.5 and >10 probes) to increase the specificity of our experiments. With these filtering criteria, we were able to thoroughly scan HMM outputs for CNV events and manually check the validity of each call by examining the normalized log intensity ratios across a chromosome. For the Agilent arrays, data analysis was performed following feature extraction using DNA analytics with ADM-2 setting according to the manufacturer's instructions. All CNVs calls were visually inspected in the UCSC genome browser.
First, we carried out validation on 24 samples from the developmental delay cohort and confirmed 117/118 HMM-inferred calls with a validation rate of 99.15%. Next, we validated 84 CNVs from an independent set of cases both validated using fluorescence in situ hybridization (FISH) and locus-specific custom high-density arrays [64] (Girirajan and Eichler, unpublished). We also validated all 44 calls from the autism cohort, 22 calls from the dyslexia cohort, and 78 calls from the developmental delay cohort. In addition, in an analysis of 517 individuals with epilepsy using this array design, 61/63 CNVs were validated on a different array platform [10].
CNV calls in autism.
CNV calls in ID.
CNV calls in NIMH controls.
CNV calls in dyslexia.
Probe densities and CNV detection threshold of hotspot v1 chip. Although the median density of the chip was designed to be approximately 2.6 kbp in the genomic hotspots and 36 kbp in genomic backbone, the limitations of the chip design (probe assignment restricted to only up to five mismatches) precluded uniform distribution of the probes throughout the genome. Therefore, the actual probe density varied across regions of the human genome. (a) The plot shows the size-wise distribution of CNVs and the density of array probes targeted to the genomic hotspots and non-hotspot regions. Note that non-hotspot regions contain two different probe densities (probe spacing of 20,000 bp and about 30,000 bp labeled a & b) and the hotspots (shaded) are covered every 10,000 bp. (b) The histogram shows the CNV detection threshold for the hotspot v1 chip. The data represent all the CNV calls obtained from analyzing cases with intellectual disability (ID). The number of CNVs detected in the aggregate at different size thresholds is shown on the Y-axis. We utilized a threshold of >10 probes, >1.5 z-score, and >50 kbp for CNV detection analysis. While we were easily able to detect events >50 kbp in the hotspot regions, we were only able to call variants ranging from 150 kbp (hotspot-associated CNVs) and 300 kbp onwards (mostly non-hotspot CNVs) with confidence (i.e., able to validate) for the non-hotspot regions.
Comparison of 9p24 deletions identified in our study to DECIPHER database. The figure shows genome browser snapshot of the 9p24 region with red and blue bars denoting deletions and duplications respectively in the DECIPHER database. Major clinical features observed in these patients are also shown. Please note that the black bars at the top denote CNVs identified in our study. PDD-NOS, Pervasive developmental delay-not otherwise specified; ID/DD, intellectual disability/developmental delay.
Diagnostic yield of different microarray reports from literature. Histograms show the number of rare CNVs (usually disease-associated) observed under different diagnostic centers. Data is shown for sample sizes >50. Data obtained from Table 2 of Miller et al., AJHG.
Chromosomal regions and probes targeted in the hotspot chip. List of all regions targeted in the hotspot chip. The list is derived from the original curation of segmental duplication regions and genomic hotspots from Bailey et al, 2002 [14].
Confirmation of CNVs arrays using custom high-density arrays. Validation of CNVs identified using NimbleGen hotspotv1 arrays (12×135 K) using a higher density 3×720K NimbleGen or 2×400K Agilent arrays.
Global analysis for CNVs in neurodevelopmental disorders. Summary and characteristics of deletions and duplications identified in the four cohorts studied.
(A) Characteristics of dyslexia cases from UW. Dyslexia measurements and scores of children tested at the UW. WATT- WRMT-R Woodcock Reading Mastery Test – Revised; Word Attack subtest. A measure of untimed reading of single non-words. WRAT3sp - Wide Range Achievement Tests – Third Addition; Spelling subtest. Spelling of single words from dictation in writing. WIAT(2)sp - Wechsler Individual Achievement Test (2nd edition); Spelling subtest. Spelling of single words from dictation in writing. WID - WRMT-R Woodcock Reading Mastery Test – Revised; Word Identification subtest. A measure of untimed reading of single words. (B) Characteristics of dyslexia cases recruited from Atlanta. Gender, phenotype and age of children recruited from the Atlanta collection is shown.
Clinical details of cases with autism (both with and without ID). Clinical features of individuals recruited through the Simons Simplex Collection (n=350) are shown.
Clinical details of cases with idiopathic ID. Clinical features of individuals with ID are shown. These individuals were recruited and evaluated at the IRCCS Associazione Oasi Maria Santissima, Troina.
Clinical features of cases with ID plus MCA. Presenting clinical features, additional malformations, and preliminary cytogenetic and genetic evaluations performed for these cases are shown.
(A) Comparison of rare CNV rates in the cohorts studied. (B) Rare CNVs in dyslexia, autism, and ID. (C) Inheritance of rare CNVs in the disease cohorts. (D) Individuals with two rare copy number variants (two hits).
Genomic disorders identified in 1,227 cases with ID, autism, and ID/MCA. Genomic disorders are defined as copy number variants that are previously identified to be associated significantly in individuals with disease compared to controls. These CNVs can either map within genomic hotspot (HS) or non-hotspot regions (non-HS).
Clinical features of a case with 6q16 deletion. Comparison of clinical features from published sources with those in the current study.
We thank Catarina Campbell, Mark Matsushita, John Wolff, Arthur Ko, Kenneth Mark, Tonia Brown, Nik Krumm, Noelani Laycock, and David A. Hughes for valuable discussions and technical assistance. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. EEE is an investigator with the Howard Hughes Medical Institute.
EEE is on the scientific advisory board for Pacific Biosciences.
This work was supported by grants from the National Institutes of Health 5R01 HD054562 to WHR and 1R01 HD065285 to EEE, a Simons Foundation grant to EEE, and in part by the Cancer Genomics Shared Resource at the Winship Cancer Institute, Emory University, to CSM. This study also makes use of data generated by the Wellcome Trust Case-Control Consortium. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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a passing resemblance
› a slightly similar appearance:
He bears more than a passing resemblance to (= he is noticeably similar to) the young Marlon Brando.
(Definition of "a passing resemblance" from the Cambridge Advanced Learner's Dictionary & Thesaurus © Cambridge University Press)
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the soft, thick hair that grows on the bodies of sheep and some other animals


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Kraftwerk At MoMA
Stylized Leaders of the Computerized Electronic Revolution at MoMA First as D.I.Y. experimenters and visionaries, then leaders in a nearly empty field, then as inspiring catalysts for man-machine marriage, Kraftwerk paved the way for millions of musicians, programmers, DJs, rappers, and fans to integrate a mechanized electronic precision into the modern musical oeuvre. At a […]
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The Instagram URL Game
This is the new best Internet game ever.
Proud to say I invented this. How to play is pretty simple - just add any word to the end of this "http://instagram.com/p/" and see if there is a picture attached to that url. The only trick is that some of the letters could be capitalized. Enjoy!
3. You can try your name
Note the random caps, just "samir" didn't come up with anything.
5. You can do regular words
7. Or do the obvious choice and be immature about it
13. Or look for famous people
See, it's easy! Good luck! Go out there and see what you can find!
- It's Day 2 of the Democratic National Convention in Philadelphia. Here's what you need to know.
- Three Qaddafi henchmen who are wanted for embezzling millions from Libya have been found living comfortably in Britain.
- ISIS has claimed responsibility for a church attack that killed a priest in northern France on Tuesday.


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Book your room at Sandies Tropical Village
Get an overview of this hotel4-star beach resort with a full-service spa
This Malindi resort is on the beach, 0.9 mi (1.4 km) from Malindi Beach, and within 12 mi (20 km) of Marine Park and Mambrui Beach. Ruins of Gedi is 12.1 mi (19.5 km) away.
Resort Features
Catch some rays at the beach or spend the day relaxing at Sandies Tropical Village's full-service spa. Then enjoy a meal at one of the resort's 2 restaurants.
Room Amenities
All 109 rooms offer ceiling fans, hair dryers, and safes.Would you like to give us feedback? Share it! Opens in a new window
Sandies Tropical VillageCasuarina Road P.O. Box 68 Malindi
Renovations & Closures
Hotel Amenities
Hotel Amenities
Sandies Tropical Village features a full-service spa and an outdoor pool. Dining is available at one of the resort's 2 restaurants. Guests can unwind with a drink at one of resort's 3 bars/lounges. Guests can enjoy a complimentary breakfast. High-speed wireless Internet access is complimentary.
This beach resort also offers gift shops/newsstands, a garden, and dry cleaning/laundry services.
- Beach sun loungers
- Beach towels
- Dry cleaning/laundry service
- Free breakfast
- Free WiFi
- Full-service spa
- Garden
- Gift shops or newsstand
- Luggage storage
- Number of bars/lounges - 3
- Number of restaurants - 2
- One meeting room
- Outdoor pool
- Television in common areas
- Total number of rooms - 109
Available in some public areas: Free WiFi
Room Amenities
- Air conditioning
- Ceiling fan
- Daily housekeeping
- Hair dryer
- In-room safe
- Phone
- Private bathroom
Where to Eat
A complimentary breakfast is offered.
Sandies Tropical Village has 2 restaurants on site.
Nearby Things to Do
The recreational activities listed below are available either on site or nearby; fees may apply.
- Snorkeling nearby
- Windsurfing nearby
- Sailing nearby
- Scuba diving nearby
- Water skiing nearby
- Parasailing nearby
Spa Services
Guests can indulge in a pampering treatment at the resort's full-service spa, Mvua Spa. Services include massages, facials, and body treatments. A variety of treatment therapies are provided, including hydrotherapy and thalassotherapy.
- Thalassotherapy treatments
- Hydrotherapy treatments
- Massages
- Body treatments
- Facial treatments
Hotel Policies
Check-in time starts at 2 PM
Check-out time is Noon
Payment types
- Pets not allowed
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
No rollaway/extra beds available
No cribs (infant beds) available
Hotel Name
- Sandies Tropical
- Sandies Tropical Village
- Sandies Tropical Village All Inclusive
- Sandies Tropical Village All Inclusive Malindi
- Sandies Tropical Village Malindi
- Tropical Village
- Planhotel Tropical Beach Hotel
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- Sandies Tropical Village Hotel Malindi
- Sandies Tropical Village Malindi, Kenya, Africa
- Sandies Tropical Village Resort Malindi
- Sandies Tropical Village Resort
- Sandies Tropical Village Malindi Kenya Africa


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Redskins Sell Naming Rights For Team HQ Sources: Isles In Talks For Arena At Belmont Park Facility Notes Islanders Potential Arena Near Citi Field? Chargers Dive Into Convention Center Possibilities MetLife Stadium Name To Stay Despite Changes Broncos Have No Stadium Naming Rights Offers Exactech Sees Value In Florida Arena Deal Facility Notes Cubs Reveal Plans For New Wrigley Suite Areas
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SBD/July 17, 2012/Facilities
Oilers Arena Project Running Over Budget, Alberta Hesitant To Chip In Extra Funds
Published July 17, 2012
MONEY TALKS: The NATIONAL POST's Jen Gerson notes the latest estimates to be presented to city council today suggest the project "could actually run to C$485-million -- unless changes are made to keep costs down." The project has "garnered almost unceasing scrutiny since it was proposed; the municipal government has agreed to a proposal that would see it foot much of the bill for the arena, although it remains short C$100-million in financing, with the province so far unwilling to chip in" (NATIONAL POST, 7/17).
IF YOU BUILD IT...: The GLOBE & MAIL's David Ebner noted Katz and Edmonton Mayor Stephen Mandel "believe the arena is an essential one-of-a-kind spark for the city's downtown, a draw for people, real-estate development and a font of new property taxes." They "want to replicate the downtown arena districts in places such as Los Angeles." Critics of the Edmonton arena deal "look at Katz's on-paper wealth and wonder why he can't just build an arena himself." Katz said that Edmontonians "underappreciate the money he has spent, and has committed." Katz: "I'm a builder. I can't say I really would have been interested in buying the team at all, but for the opportunity, through the team, to do such a transformational thing for the city, and also sustain the team, and sustain the NHL, and build a new arena, and revitalize the city. It was the whole kind of thing that was really attractive to me. I didn't have a burning desire to own a hockey team" (GLOBE & MAIL, 7/14).


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Nikon J1 vs Sony NEX 5
Started Dec 30, 2011 | Discussions thread
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Identity • Senior Member • Posts: 1,065
Re: Nikon J1 vs Sony NEX 5
In reply to Confused of Malvern • Dec 31, 2011
I had an NEX-3, and now have a Nikon V1. The NEX has better ultimate image quality, but was too slow to keep up with our toddler. The V1 is great for photographing kids. You will have to take it out of auto-everything mode to get the best results, but as long as you understand when to use single-shot or continuous autofocus, use center-point focus, and adjust ISO manually in dim lighting, you can get great results. Even with the relatively slow kit lens, I've gotten some great shots indoors without a flash. Shooting at 5fps and just keeping the best shots is pretty handy.
As a bonus, the Nikon 1 cameras take excellent videos with fast, continuous auto-focus. It's the first still camera that I've had that can replace a camcorder for me.
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text: Took my wife here for lunch for her birthday. It was expensive (as expected) and the food whilst fresh and delicious, was very small servings. You definitely need to eat 3 courses to be full and expect to pay Euros 200+ for that. There are nicer places to eat in Venice.


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Addicted to Dimes (Confessions of a Liar and a Cheat)by Catherine Townsend-Lyon
Based on a true story, told in the author's own words, without polish or prose, a haunting tale of addiction and....
Based on a true story, told in the author's own words, without polish or prose, a haunting tale of addiction and....
Product Details
- 9780984478484
- Publisher:
- Kodel Group, LLC, The
- Publication date:
- 11/02/2012
- Pages:
- 226
- Product dimensions:
- 6.00(w) x 9.00(h) x 0.52(d)
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Addicted to Dimes (Confessions of a Liar and a Cheat) based on 0 ratings. 4 reviews.
This book is a great find! Although it explains in depth the authors personal struggles with her "Gambling" addiction, it could equally apply to anyone else who has an addiction that is taking over their life. The book flows naturally as though she is sitting in a coffee shop telling you herself. Written from her own perspective she as an uncanny way of taking the reader along her life journey with her. You can't help but understand and sympathise with the authors struggle with (in her case gambling) addiction. Either way, a MUSTread for anyone who is or knows someone who is struggling with an addiction in their own life.
If anyone you know has a gambling problem, or any addiction, this book is a Must Read. I had no Clue how dangerous this could be for some of the population who may have compulsive behaviors. Her story shows the Slow Slide, and progression, this addiction can have on a person. Great Read!
Hemingway is right: "There is nothing to writing. All you do is sit down at a typewriter and bleed." And bleed she does. Catherine Townsend-Lyon writes her story honestly and boldly. Her purpose is to share her story so others may benefit. Her story resonates with the reader even if the reader doesn't have an addiction problem. Because of my reading Addiction to Dimes, I am contacting my daughter who chooses not to have family contact. I want her to know that she is loved. Catherine's story validates the importance of love and acceptance that we all need. Sharon L. Hicks
I was so impressed by Catherine's story and how she was extremely open and candid about everything she went through regarding her addiction to compulsive gambling. I found her book to be brutally honest, and could not help but root for her to come out of her past troubles a better person. The fact that she is able to help others in a similar situation is a true testament to her will to live and thrive. I definitely recomment this book to anyone who is an addict, or in the mood to read an authentic feel good story!


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Jen Gatien - Tuesday 16th September 2008 at Village East Cinema New York City, USA (2 Pictures)
Jen Gatien
Photo credit: PNP/ WENN
Jen Gatien
Photo credit: PNP/ WENN
View All: Jen Gatien - Tuesday 16th September 2008...
Next Jen Gatien Slideshow: Buddha bar celebrates its one year anniversary party - New York City, USA - Wednesday 9th May 2007
The 1969 session, including the only known recording of 'Sunshine Woman' by the band, will be included on a re-issue of 'The Complete BBC Sessions'...
The 55 year old actor joined Chris Martin and co. on stage in New Jersey to perform 'Earth Angel' and 'Johnny B. Goode'.
Bjork Digital comes to London's Somerset House in September, along with a single live show at the Royal Albert Hall.
Kim Kardashian released an audio excerpt from a phone call between Kanye and Taylor Swift over the lyrics of 'Famous' - but if it was recorded...
There's very much a strength of conviction in remaining what you were, but arguably more so in becoming what you want to be.
The BBC drama starring Aidan Turner returns to BBC One on September 4th.
Guns N' Roses were detained at the Canadian border last week for gun possession but they're adamant the weapon didn't belong to them.
One of those mopey independent dramas that drifts through a mere hint of a plot,...
Inspired by true events, this darkly involving drug-ring drama holds our interest mainly because we...


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Our Summer of Proclamation Series will continue next Sunday, August 19th, at the 11:00 am service as we welcome Ascension parishioner and EfM student Meredith Ward to the pulpit. Please join us as Meredith shares her perspective on our scripture readings.
Services at AscensionAscension is a welcoming, diverse, and inclusive community of people who gather to proclaim the Good News of Jesus Christ, to give praise and thanks to God through the beauty of worship, and to love and serve God and our neighbors.
Due to anticipated heat, the 11 a.m. service this Sunday, July 31, will be held in the air-conditioned Parish Hall at 12 W. 11th Street, around the corner from the church.
- Regular Worship Schedule
- Sunday 9am: Holy Eucharist at Side Altar
- Sunday 11am: Holy Eucharist in the Parish Hall with sermon, hymns & soloist
- Sunday 7pm: Service of Meditations and Sacrament, including chant, interfaith readings and communion
- Monday – Friday: 6pm at Side Altar
We'd like to hear from you!
From our Pulpit
Sermon – July 24, 2016by Seminarian Nick Walters
Four weeks ago, I arrived as a guest at the Church of the Ascension; this week, I leave as your friend. On Friday, I was privileged to have dinner, among other wonderful people, with your Presiding Bishop, Michael Curry. During our conversation, I was asked to identify one of the defining features…
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Sermon – July 17, 2016by The Rev. Elizabeth G. Maxwell
Almighty God, the fountain of all wisdom, you know our necessities before we ask and our ignorance in asking: Have compassion on our weakness, and mercifully give us those things which for our unworthiness we dare not, and for our blindness we cannot ask; through the worthiness of your Son Jesus Christ our Lord, who lives and reigns with you and the Holy Spirit, one God, now and for ever. Amen.
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Abahani annihilate MohammedanNazmul Hossain Shanto, Abahani's young batsman, stayed for a while at the crease as he was disappointed with the caught-behind decision. The left-hander pointed to his shoulder while returning to the dressing room and at that time Abahani were 64 ... Bangladesh Daily Star, 1 month ago
Abahani thump sorry Mohammedan - Dhaka Tribune, 1 month ago
Abahani beat Mohammedan by 260 runs, Rupganj take solo lead - Financial Express Bangladesh, 1 month ago
21 images for nazmul hossain
Minister Mosharraf asked to surrender
The High Court yesterday directed Housing and Public Works Minister Mosharraf Hossain to surrender before a lower court in six weeks in a corruption case filed on charges of amassing illegal wealth worth Tk 3 crore. It also cancelled its 2008 ...Bangladesh Daily Star, 1 week ago
Abahani-Doleshwar match scrapped
Bangladesh Cricket Board president Nazmul Hasan (2nd-R) speaks during a press conference at Mirpur on Wednesday. — New Age photo The Bangladesh Cricket Board on Wednesday declared the halted Dhaka Premier League match between Abahani Limited ...New Age Bangladesh, 1 month ago BCB hell-bent on 2-tier selection policy New Age Bangladesh, 1 month ago BCB's passing fancy? Dhaka Tribune, 1 month ago
From troubled Pirojpur youth to an adept IT businessman
Ferdous Hossain from Uttar Shankarpasa village in Pirojpur sadar upazila was a meritorious student. In class V, he secured a scholarship. But after completing his Higher School Certificate, as youth too often do, Ferdous took a few missteps in life.Bangladesh Daily Star, 1 month ago
Govt urged to develop mechanism to implement PIL verdicts
Jurist Kamal Hossain speaks at a discussion on public interest litigation challenge and opportunities organised by rights organisations at CIRDAP auditorium in Dhaka on Saturday. — New Age photo Supreme Court judges, jurists and right activist ...New Age Bangladesh, 1 month ago
Mosaddek guides Abahani in thriller
Abahani Limited's Mosaddek Hossain flays one through the off side during their Dhaka Premier League match against Prime Doleshwar Sporting Club at BKSP yesterday ` Photo- MAINOOR ISLAM MANIK Mosaddek Hossain kept Abahani Limited well on track ...Dhaka Tribune, 2 months ago Mosaddek seals cliffhanger for Abahani New Age Bangladesh, 2 months ago Controversial umpiring mars league New Age Bangladesh, 1 month ago
Agri income stimulates non-farm sector in rural areas: WB study
World Bank country director for Bangladesh, Nepal and Bhutan Qimiao Fan speaks while LGRD minister Khandakar Mosharraf Hossain and General Economics Division of the Planning Commission member Shamsul Alam, among others, look on at the launching of a ...New Age Bangladesh, 2 months ago
HC gives go ahead to cadet Pollen's murder case
The bench of Justice M Enayetur Rahim and Justice Amir Hossain dropped a petition filed by four accused seeking a stay on the trial proceedings of the case. Sharmila Shaharin Pollen, 18, a second-year student and daughter of retired Air Force ...Bangladesh Daily Star, 2 months ago
BNA to take part in 14-party programme
DHAKA, June 13, 2016 (BSS) - Bangladesh National Alliance (BNA) led by Barrister Nazmul Huda will participate in all the programmes of Awami League-led 14-pary alliance expressing solidarity with them. This was disclosed by spokesman of the ...Bangladesh Sangbad Sangstha, 1 month ago 14-party vows to build militancy-terrorism free country Bangladesh Sangbad Sangstha, 2 weeks ago
Be united to wipe off terrorism
FARIDPUR, July 3: Local Government Minister Engineer Khondoker Mosharraf Hossain urged all to be united and help the government to fight terrorism. He sought the cooperation of the people to fulfil the dream of Sheikh Hasina who is relentlessly ...Financial Express Bangladesh, 3 weeks ago Mosharraf urges all to be united under Awami League Bangladesh Sangbad Sangstha, 3 weeks ago
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Datsun GO hits road at starting price of Rs3.12 lakh
Japanese auto major Nissan on Wednesday introduced its Datsun brand hatchback 'GO', priced between Rs3.12 lakh and Rs3.69 lakh (ex-showroom, Delhi).
"With Datsun we are entering a segment, which we can't address with the Nissan brand. We expect the Datsun brand to contribute half to one-third of Nissan's sales in India," said Nissan Motor India MD and CEO Kenichiro Yomura while talking to The Pioneer.
The company will launch three models under the Datsun brand by FY'16 and discolosed that Oragadum plant, which has a production capacity of 4 lakh units annually, will reach its full capacity with the manufacturing of Datsun GO.When asked about the export plans for the product, Yomura said: "There are no immediate plans to export the car. But if there is an opportunity we can have a look at it".
Datsun products will be available at Nissan dealerships and the company currently has 125 dealerships across the country."It will be retailed through a fully-branded environment within Nissan's dealership network across the country," Yomura added.Datsun GO has fuel efficiency of 20.64 km per litre and comes with various features including electronic power steering, front power windows and mobile docking station.
The launch of Datsun comes at a time when Nissan Motor India has plans to introduce 10 new models in India by 2016.The company is targeting to garner a 10 per cent market share in the automobile industry by 2016. It has also proposed to increase dealership networks to 300.Nissan Motor would sell the Datsun GO and other models from the Datsun range on its own in India. Besides Datsun, Nissan Motor India currently retails hatchback Micra, sedan - Sunny, SUV Terrano, among others.
- Donuts in flight in first US-approved drone delivery 23 Jul 2016 | AFP
- Twitter will not Periscope its quarterly earnings results 23 Jul 2016 | IANS
- Tata Metaliks net profit rises 26% in Q1 23 Jul 2016 | IANS
- India is youngest start-up nation with 72% founders below 35 years: Sitharaman 23 Jul 2016 | IANS
- Prabhu to inaugurate first green train corridor on Sunday 23 Jul 2016 | IANS
- India ranks 110th on Sustainable Development index 22 Jul 2016 | PTI
- VIA turns 10 in style, expects 50 million users at 10th anniversary sale 22 Jul 2016 | Agencies
- Axis Bank Q1 profit dips 21% at Rs 1,556 cr 22 Jul 2016 | PTI
- Post-Brexit India a safe haven for investors: Jaitley 22 Jul 2016 | IANS
- Sensex climbs 73 pts on Asian cues 21 Jul 2016 | PTI
Apocalypse now
24 Jul 2016 | Ananya Borgohain
A cloudburst can paralyse a megacity like Delhi, a cyclone can wreak catastrophe in Mumbai, that also has a nuclear facility, and an epic flood can decapacitate Kolkata anytime. All threats posed by climate change are no more in the future...
BJP demonstrate against BSP leaders
24 Jul 2016 | PNS | Lucknow
On the defensive for the last two days over profane remarks by sacked vice-president Dayashanker Singh against BSP chief Mayawati, the BJP upped its ante on Saturday by demonstrating across UP against foul language used by protesting BSP leaders against Singh's wife and minor daughter. In Lucknow, BJP workers fought a pitched battle with the police when they were stopped by the men in uniform from taking out a protest march...
My dear youths, nepotism and the poison of casteism will not help in development. Support politics of vikasvad (development).
Peace TV was refused (broadcast rights) for security reasons. There are many Hindu and Christian channels in India, but no Islamic channel.
I had never ever desired or thought that I would get to sing the national anthem. I feel blessed and honored. I was very nervous.


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Sleep Inn Jessup, Jessup
- Free buffet breakfast, free WiFi, and free parking
Main amenities
- 54 guestrooms
- Fitness center
- Business center
- 24-hour front desk
- Coffee/tea in a common area
- Air conditioning
- Daily housekeeping
- Free newspapers in the lobby
What's around
- Heart of Jessup
- Historic Savage Mill (3 mi / 4.8 km)
- Laurel Park (5 mi / 8 km)
- National Security Agency Headquarters (5.7 mi / 9.1 km)
- Laurel College Center (5.7 mi / 9.2 km)
- Laurel Museum (5.8 mi / 9.3 km)
For families
- Free cribs/infant beds
- Rollaway/extra beds (surcharge)
- Microwave
- Refrigerator
- Premium TV channels
- Free toiletries
Sleep Inn Jessup, Jessup
Hotel Info: 866-539-8117from $95
- Standard Room, 2 Queen Beds, Smoking
- Standard Room, 2 Queen Beds, Non Smoking
- Standard Room, 1 King Bed, Smoking
- Standard Room, 1 King Bed, Non Smoking
Also popular with travelers from the USA
At a glance
Key facts
Hotel size
- This hotel has 54 rooms
- This hotel is arranged over 3 floors
- Check-in time 3 PM-Midnight
- Check-out time is 11 AM
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Children (18 years old and younger) stay free when occupying the parent or guardian's room, using existing bedding
- Pets not allowed
- Free WiFi and wired Internet access in public areas
- Free WiFi and wired Internet access in rooms
- Free self parking
Nearby Two Star Jessup hotels
In the hotel
- Free buffet breakfast
- Coffee/tea in a common area
- Fitness facilities
- Business center
- 24-hour front desk
- Free newspapers in lobby
- Elevator/lift
- In-room accessibility
- Roll-in shower
In the room
- Air conditioning
- Coffee/tea maker
- Iron/ironing board
- Free toiletries
- Hair dryer
- Premium TV channels
- Desk
- Free weekday newspaper
- Free WiFi
- Free local calls
- Refrigerator
- Microwave
- Daily housekeeping
- In-room safe
Top Jessup hotels
Recently reviewed hotels in Jessup
- Embassy Suites Hotel Baltimore at BWI AirportFrom
"My stay was comfy and pleasant. The staff was nice and helpful"Jul 25, 2016
- Holiday Inn Rosslyn at Key BridgeFrom
"Great hotel with easy access to a metro stop and quick walk into Georgetown!"Jul 25, 2016
- Ramada Limited CockeysvilleFrom
"Accommodating for price On booking if handicapped insist on a ground floor and a shower with safety bars."Jul 25, 2016
- Embassy Suites by Hilton Washington D.C. – Convention CenterFrom
"It was very good. Keep it up. Service was good. Breakfast was excellent . Happy hour was outstanding."Jul 25, 2016
Nearby hotels
Sleep Inn Jessup, Jessup's small print
Also known as
- Sleep Inn Hotel Jessup
- Sleep Inn Jessup
Optional extras
Rollaway beds are available for USD 10.00 per night
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Good 3.9 /5 from 45 reviews
My hotel should not have hidden fees.
It was clean in the Lobby which makes you think the rooms will be clean but they were not. They had POOR/Rude customer service. An Employee walked in are room when it wasn't even check out time yet. I do not recommend this hotel. There are plenty of competitor hotels near that will provide better customer service. Poor customer service makes you feel uncomfortable.
hated it. hotel didn't have my reservation and said it wasn't their fault. I even watched them ignoring the phone call from hotels.com who tried to remedy the situation. Very rude workers and owners. They had overbooked their rooms and did not even apologize for the inconvenience
Nice for the price . Clean and comfortable . Parking a problem as trucks took up too many spaces .
The hotel is nice and easily accessible, there was a small shopping plaza with supermarket, food, and a dollar store within walking distance. The hotel staff was not the most friendly, but yet pleasant.
Is the description of this hotel not correct? Tell us


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Norman Osborn may be running the show, but not every super-villain is going to accept the new world order. But who -- or what -- is ZODIAC? In this dark, brooding tale that snakes through the underbelly of the modern Marvel Universe, the new breed of super-villain has finally arrived! The order of the day is "mischief for mischief's sake," and no one -- neither hero *nor* villain -- is safe!
Confirmed: Geoff Johns Is the New President of DC Entertainment
Comic Books, Film, TV


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Overhaul Your Whole Wardrobe With This Stellar Sample Sale
The arrival of a new season makes us long for a style reboot. And if you're pining for a new stash of summer wares, then you'd best not pass up this style-packed sample sale!
We recommend you scoop up everything from Wren's low-key and ultra feminine pieces to uniquely designed cuffs, rings, and necklaces by Unearthen and ACB. Plus, don't miss out on the über-chic neoprene swimsuits, backpacks, and totes from Alexandra Cassaniti, and those oh-so coveted shoes by LD Tuttle.
If you were shopping retail, these styles would cost quite the pretty penny — but for two days only, you can score them all for up to 80% off. Yup, that's right, up to 80% off. So, consider this the perfect opportunity to re-vamp the ol' wardrobe — at an affordable price — for all those BBQs, beach jaunts, and whatever other affairs (sexy dates?) summer brings your way.
When: Friday, June 8, noon to 6 p.m. and Saturday, June 9, 10 a.m. to 3 p.m.
Where: 1313 Palmetto Street (at Mateo Street); no phone.
Where: 1313 Palmetto Street (at Mateo Street); no phone.
Photo: Via Wren
- Los Angeles | Wren Sample Sale - LA Sample Sales
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Thank you for your wonderful review. It was a real pleasure hosting the both of you. We really hope that we see you both in the near future. Sincerely, Susan and Bruno
Perfect attentive service started as soon as we were collected at the airport and continued for the entire weekend of our holiday . Nothing is too much trouble for the owners Sue & Bruno who more than provided everything they promised and more . Luxurious and beautiful accommodation set in enclosed gardens with stunning views and high quality furnishings and...
Thank you Thank you Thank you, for spending your girly holiday with us again ! It was a real pleasure hosting all of you. We will see you all next year ... Same Time, Same Place !
Thank you for you're lovely review.
It was our pleasure to host you and you family, we loved your children.
So happy that you had a great time relaxing and having fun in the pool with the kids.
We aim to see the smiling faces of your guests, and at this point we know we have helped make your vacation...
Rates are calculated based on the latest information provided. Please contact the manager/owner to confirm actual rates for your requested dates.


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- Swimmer Ryan Lochte reveals one of his worst dates - US Weekly
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- Despite rumors, Eddie Murphy's daughter is not pregnant - Gossip Cop
- The Vampire Diaries star Michael Trevino steps out for a good cause - Just Jared Jr
- Are Blac Chyna and Kylie Jenner on good terms? - Radar
- Blue Ivy is just as stylish as her mom Beyonce! - Lainey Gossip
- This Narcos star confirms he's not coming back for another season of the show - The Hollywood Reporter
29 August 2013 at 12:51 PM
Blake Lively Takes Ryan Reynold's Dog Baxter to the Park!
About this photo set: Blake Lively treats Ryan Reynolds' dog Baxter to some playtime at a local park on Monday (August 26) in Bedford, NY. The 26-year-old actress and her pup were… Read More Here
Photo #: 2940066
Posted to Blake Lively, Celebrity Pets
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Summer is Here...Time to Get Cooking!
Learn something new this summer: breadmaking, pastry, pasta, knife skills and much more
New Baking Classes with Richard Bertinet
Choose from English, American or Nordic baking or book all 3 at a discount. 24-26 Aug.
As the Romans Do
Join the wonderful Eleonora Galasso for this exciting class inspired by vibrant city of Rome. Saturday, 1st October 2016
Latest News
- New Class - Contemporary Irish Cooking with Clodagh McKenna
1st June 2016
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