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Item does not contain fulltext, Background: The International Trauma Questionnaire (ITQ) is a recent self-report measure to assess the severity and probable posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) as defined by the 11th revision of the International Classification of Diseases. Few studies have examined the psychometric properties of full and short ITQ versions in depth. Therefore, we aimed to evaluate the psychometric properties of the Dutch-translated 28-item ITQ and the 12-item version. Method: Data were used from existing clinical studies and routine clinical assessments for the 28-item (n = 956) and 12-item (N = 4,944) ITQ versions in trauma-exposed treatment-seeking individuals in the Netherlands. Internal consistency and factor validity were assessed, and rates of probable PTSD and CPTSD were estimated. In addition, convergent and discriminant validity were examined by correlations with similar and dissimilar measures. Results: Both versions of the ITQ showed good internal consistency and convergent validity. Confirmatory factor analysis showed that both a first-order correlated six-factor model and a two-factor second-order model were a good representation of the latent structure for the ITQ-12. The ITQ-12 resulted in higher CPTSD rates compared to the ITQ-28 (47% vs. 36.3%), while a similar number of patients met the criteria for either PTSD or CPTSD (70.6% vs. 76.4%). Conclusion: Internal consistency and convergent validity for the ITQ-12 and ITQ-28 were supported. The factorial validity was good for the ITQ-12 and acceptable for the ITQ-28. The discrepancy in CPTSD rates between the ITQ-12 and ITQ-28 calls for further testing of scoring methods against diagnostic clinical interviews for CPTSD., 02 november 2023, 10 p.

Contains fulltext : 229260.pdf (publisher's version ) (Open Access), Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Contains fulltext : 198351.pdf (publisher's version ) (Open Access), Background: In 2013, the Clinician-Administered PTSD Scale, the golden standard to assess PTSD, was adapted to the DSM-5 (CAPS-5). Objective: This project aimed to develop a clinically relevant Dutch translation of the CAPS-5 and to investigate its psychometric properties. Method: We conducted a stepped translation including Delphi rounds with a crowd of 44 Dutch psychotrauma experts and five senior psychotrauma experts. Using partial crowd-translations, two professional translations and the official Dutch translation of the DSM-5, each senior expert aggregated one independent translation. Consensus was reached plenary. After back-translation, comparison with the original CAPS-5 and field testing, a last round with the senior experts resulted in the final version. After implementation clinicians conducted CAPS-5 interviews with 669 trauma-exposed individuals referred for specialized diagnostic assessment. Reliability of the Dutch CAPS-5 was investigated through internal consistency and interrater reliability analyses, and construct validity through confirmatory factor analysis (CFA). Results: CAPS-5 total severity score showed high internal consistency (alpha = .90) and interrater reliability (ICC = .98, 95% CI: .94-.99). CAPS-5 diagnosis showed modest interrater reliability (kappa = .59, 95% CI: .20-.98). CFA with alternative PTSD models revealed adequate support for the DSM-5 four-factor model, but a six-factor (Anhedonia) model fit the data best. Conclusions: The Dutch CAPS-5 is a carefully translated instrument with adequate psychometric properties. Current results add to the growing support for more refined (six and seven) factor models for DSM-5 PTSD indicating that the validity and clinical implications of these models should be objective of further research.

Contains fulltext : 199183.pdf (publisher's version ) (Closed access), It has been hypothesized that adult attachment representations guide caregiving behavior and influence parental sensitivity, and thus affect the child's socio-emotional development. Several studies have shown a link between posttraumatic stress disorder (PTSD) and reduced parental sensitivity, so it is possible that PTSD moderates the relationship between insecure attachment representations and insensitivity. In this study symptoms of PTSD (Harvard Trauma Questionnaire), parental sensitivity (Emotional Availability Scales), and attachment representations (Attachment Script Assessment) were assessed in 53 parents who were asylum seekers or refugees. Results showed that when parents were less able to draw on secure attachment representations, symptoms of PTSD increased the risk of insensitive parenting. These findings suggest that parental sensitivity is affected not just by attachment representations, but by a conjunction of risk factors including symptoms of PTSD and insecure attachment representations. These parents should therefore be supported to establish or confirm secure models of attachment experiences, to facilitate their ability interact sensitively and form a secure relationship with their children.

Background: Many sources describe the importance of the therapeutic alliance on the effect of psychological treatment. The therapeutic alliance could form a valuable predictor in the treatment of PTSD (-related symptoms). Also, outcome research indicates that the general trajectory of change in successful psychotherapy is highly predictable. Literature suggests that the predictability of treatment- outcome could differ for patients with different traumatization backgrounds. Aims: The aim of the current study was to determine whether therapeutic alliance can predict change in overall psychological wellbeing in the treatment of complex traumatized patients and if the change in overall psychological wellbeing during the first phase of treatment is indicative for overall treatment outcome. This study also focused on identifying differences between groups with different traumatization backgrounds (postwar generation, veterans, occupational, asylum-seekers and refugees and other) in the change of overall psychological wellbeing (deteriorated, unchanged or improved) during overall treatment. Methods: Ninety-two patients of Foundation Centrum ’45 participated in the current study, by regularly completing the Outcome- and Session Rating Scale. Results: The results indicate that therapeutic alliance can predict change in overall psychological wellbeing. Results further show that, for change in overall psychological wellbeing, the conditions ‘deteriorated’ and ‘unchanged’ are most predictable. Results show that across all groups, the conditions ‘no change’ and ‘deterioration’ are most predictable. Conclusion: The results of the study confirm the value of therapeutic alliance on the change in overall psychological wellbeing. Further, it was confirmed that change in overall psychological wellbeing of the overall treatment course can be predicted relatively well based on the type of change during the beginning of treatment. Future research is needed with a focus on bigger sample

Contains fulltext : 167655.pdf (publisher's version ) (Closed access), We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases.

Contains fulltext : 154362.pdf (publisher's version ) (Closed access), AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3' transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder.

Contains fulltext : 155287.pdf (publisher's version ) (Open Access), BACKGROUND: Identification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum. METHODS: Whole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed. RESULTS: A de novo KCND3 mutation (c.877_885dupCGCGTCTTC; p.Arg293_Phe295dup) was found duplicating the RVF motif and thereby adding an extra positive charge to voltage-gated potassium 4.3 (Kv4.3) in the voltage-sensor domain causing a severe shift of the voltage-dependence gating to more depolarized voltages. The patient displayed a severe phenotype with early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. CONCLUSIONS: We identified a de novo KCND3 mutation causing the most marked change in Kv4.3's channel properties reported so far, which correlated with a severe and unique spinocerebellar ataxia (SCA) type 19/22 disease phenotype.

Contains fulltext : 137247.pdf (publisher's version ) (Closed access), Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.

Contains fulltext : 125776.pdf (publisher's version ) (Closed access), The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.

In this thesis we apply Hidden Conditional Random Fields (HCRF) to action recognition. HCRF is a classification method modelling the structure among local observations. In our system, an image is modelled as a set of hidden part labels conditioned on their local features. For each action class, the probability of an assignment of part labels to local patch features is modelled by a Conditional Random Field (CRF). These class conditional CRFs are combined into an unified framework of HCRF, which treats the assignment of part labels as hidden variables. This model also combines the local patch features with the global feature of an image under the framework of HCRF. The model parameter is trained with a maximum likelihood criteria. We have also evaluated a baseline model of HCRF, called the root model. It only uses the global feature and it does not include the hidden part labels. The root model is trained with the maximum likelihood criteria as well. An extension of HCRF, Max-Margin Hidden Conditional Random Field (MMHCRF), has also been applied to action recognition. MMHCRF extends HCRF by training with a maximum margin criteria. That is, it sets the model parameter in the way that the margin between the score of the correct action label and the scores of the other labels is maximized. We have also evaluated a baseline model of MMHCRF. Similar to the root model, this baseline model only uses the global feature, but it trains the model parameter with the max-margin criteria. Based on HCRF and the root model, we have proposed a Part Labels method. This method learns the hidden part labels of each image using the model parameter trained by HCRF. It uses these part labels as a new set of local features and combines them with the global feature. It trains these features in the same way as the root model. We have implemented and evaluated these five models on the Weizmann dataset, a human action dataset, and an animal behaviour dataset, called Noldus ABR dataset. Our expe

Facial expressions are essential in human face-to-face communication because they reflect emotion and are a form of nonverbal communication. The face of a human has the most relevant visual characteristics of personality and emotion. We developed and analyzed a real-time fully automatic facial expression classification system that uses sequences of frames describing the dynamics of the expressions. This includes face detection, face registration using landmark points of the face, feature extraction using optical flow and finally classification between six basic expressions. Extensive experiments on the Cohn-Kanade database illustrate that this approach is effective for facial expression analysis. The contributions of this paper are twofold: (1) to have a fully automated way to measure spontaneous facial expressions and (2) to incorporate optical flow to cope with temporal information to enhance the overall recognition results. The results of the classification indicate that the correct alignment has a significant effect on the accuracy of the system.

Contains fulltext : 118541.pdf (publisher's version ) (Closed access), AnkyrinG, encoded by the ANK3 gene, is involved in neuronal development and signaling. It has previously been implicated in bipolar disorder and schizophrenia by association studies. Most recently, de novo missense mutations in this gene were identified in autistic patients. However, the causative nature of these mutations remained controversial. Here, we report inactivating mutations in the Ankyrin 3 (ANK3) gene in patients with severe cognitive deficits. In a patient with a borderline intelligence, severe attention deficit hyperactivity disorder (ADHD), autism and sleeping problems, all isoforms of the ANK3 gene, were disrupted by a balanced translocation. Furthermore, in a consanguineous family with moderate intellectual disability (ID), an ADHD-like phenotype and behavioral problems, we identified a homozygous truncating frameshift mutation in the longest isoform of the same gene, which represents the first reported familial mutation in the ANK3 gene. The causality of ANK3 mutations in the two families and the role of the gene in cognitive function were supported by memory defects in a Drosophila knockdown model. Thus we demonstrated that ANK3 plays a role in intellectual functioning. In addition, our findings support the suggested association of ANK3 with various neuropsychiatric disorders and illustrate the genetic and molecular relation between a wide range of neurodevelopmental disorders.

1 mei 2012, Contains fulltext : 110552.pdf (publisher's version ) (Closed access), In a male patient with West Syndrome we identified a perfectly balanced, de novo balanced translocation 46,XY,t(2;6)(p15;p22.3). No known protein coding genes were disrupted by the translocation and positional effects on nearby genes were excluded by expression studies. A putative long non-coding RNA, BX118339, spans the breakpoint on chromosome 6. It can be hypothesized that disruption of this non-coding transcript plays a role in the pathogenesis of the patient.

1 mei 2010, Contains fulltext : 88561.pdf (publisher's version ) (Closed access), BACKGROUND: Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. METHODS: Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. RESULTS: Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. CONCLUSIONS: The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.

Contains fulltext : 81654.pdf (publisher's version ) (Closed access), Beals-Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23-34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2-positive patients. In our FBN2-positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z-score: 4.09) and his father (z-score: 2.94), warranting echocardiographic follow-up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2-negative patients in this cohort were clinically indistinguishable from all published FBN2-positive patients harboring a FBN2 mutation, suggesting locus heterogeneity.

Contains fulltext : 80657.pdf (publisher's version ) (Closed access), BACKGROUND: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. METHODS: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. RESULTS: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. CONCLUSIONS: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnosti

Contains fulltext : 76802.pdf (publisher's version ) (Closed access), This study examined the associations between adolescents' daily Internet use and low well-being (i.e., loneliness, low self-esteem, and depressive moods). We hypothesized that (a) linkages between high levels of daily Internet use and low well-being would be mediated by compulsive Internet use (CIU), and (b) that adolescents with low levels of agreeableness and emotional stability, and high levels of introversion would be more likely to develop CIU and lower well-being. Data were used from a sample of 7888 Dutch adolescents (11-21 years). Results from structural equation modeling analyses showed that daily Internet use was indirectly related to low well-being through CIU. In addition, daily Internet use was found to be more strongly related to CIU in introverted, low-agreeable, and emotionally less-stable adolescents. In turn, again, CIU was more strongly linked to loneliness in introverted, emotionally less-stable, and less agreeable adolescents.

Contains fulltext : 80644.pdf (publisher's version ) (Closed access), Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.

Contains fulltext : 69531.pdf (publisher's version ) (Closed access), BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.