Het verband tussen fonologische vaardigheden, voorbereidende rekenvaardigheden en korte-termijn geheugen bij jonge kinderen met een genetisch risico op dyslexie

Ontwikkelingsdyslexie (hierna te noemen: dyslexie) is een specifieke stoornis die leidt tot lees- en spellingsproblemen. Onderzoek heeft laten zien dat dyslexie vaak samen voorkomt met dyscalculie, een specifieke rekenstoornis. In dit onderzoek werd onderzocht of de co-morbiditeit tussen dyslexie en dyscalculie ook op jonge leeftijd te vinden is. Tevens werd onderzocht of een eventueel verband te verklaren is vanuit een tekort in de fonologische lus van het werkgeheugen. Hiertoe zijn de fonologische vaardigheden, voorbereidende rekenvaardigheden en capaciteit van de fonologische lus van het werkgeheugen van 23 kinderen met een genetisch risico op dyslexie vergeleken met die van 11 controlekinderen. Alle kinderen zaten ten tijde van het onderzoek in het einde van groep 2. Resultaten laten zien dat relatief meer risicokinderen slecht presteren op het herkennen en benoemen van letters. Bovendien scoorde de risicogroep slechter op een toets voor getalbegrip. Verder werd er een overlap gevonden tussen fonologische problemen en problemen met voorbereidende rekenvaardigheden. Deze overlap kon echter niet verklaard worden door een tekort in de fonologische lus van het werkgeheugen. Deze data benadrukken het belang van vroege diagnostiek aangezien er kinderen zijn die al op jonge leeftijd meerdere leerproblemen ondervinden

Het verband tussen fonologische vaardigheden, voorbereidende rekenvaardigheden en korte-termijn geheugen bij jonge kinderen met een genetisch risico op dyslexie

Ontwikkelingsdyslexie (hierna te noemen: dyslexie) is een specifieke stoornis die leidt tot lees- en spellingsproblemen. Onderzoek heeft laten zien dat dyslexie vaak samen voorkomt met dyscalculie, een specifieke rekenstoornis. In dit onderzoek werd onderzocht of de co-morbiditeit tussen dyslexie en dyscalculie ook op jonge leeftijd te vinden is. Tevens werd onderzocht of een eventueel verband te verklaren is vanuit een tekort in de fonologische lus van het werkgeheugen. Hiertoe zijn de fonologische vaardigheden, voorbereidende rekenvaardigheden en capaciteit van de fonologische lus van het werkgeheugen van 23 kinderen met een genetisch risico op dyslexie vergeleken met die van 11 controlekinderen. Alle kinderen zaten ten tijde van het onderzoek in het einde van groep 2. Resultaten laten zien dat relatief meer risicokinderen slecht presteren op het herkennen en benoemen van letters. Bovendien scoorde de risicogroep slechter op een toets voor getalbegrip. Verder werd er een overlap gevonden tussen fonologische problemen en problemen met voorbereidende rekenvaardigheden. Deze overlap kon echter niet verklaard worden door een tekort in de fonologische lus van het werkgeheugen. Deze data benadrukken het belang van vroege diagnostiek aangezien er kinderen zijn die al op jonge leeftijd meerdere leerproblemen ondervinden

Does familial risk for alcohol use disorder predict alcohol hangover?

Positive family history of alcohol use disorder (FHP), a variable associated with propensity for alcohol use disorder (AUD), has been linked with elevated hangover frequency and severity, after controlling for alcohol use. This implies that hangover experiences may be related to AUD. However, inadequate control of alcohol consumption levels, low alcohol dose and testing for hangover during the intoxication phase detract from these findings. Here, we present further data pertinent to understanding the relationship between family history and alcohol hangover. Study 1 compared past year hangover frequency in a survey of 24 FHP and 118 family history negative (FHN) individuals. Study 2 applied a quasi-experimental naturalistic approach assessing concurrent hangover severity in 17 FHP and 32 FHN individuals the morning after drinking alcohol. Both studies applied statistical control for alcohol consumption levels. In Study 1, both FHP status and estimated blood alcohol concentration on the heaviest drinking evening of the past month predicted the frequency of hangover symptoms experienced over the previous 12 months. In Study 2, estimated blood alcohol concentration the previous evening predicted hangover severity but FHP status did not. FHP, indicating familial risk for AUD, was not associated with concurrent hangover severity but was associated with increased estimates of hangover frequency the previous year

Transformed canine and murine mesenchymal stem cells as a model for sarcoma with complex genomics

Simple SummarySarcomas are rare cancers of mesenchymal origin, the majority of which are characterized by many copy number alterations, amplifications, or deletions. Because of these complex genomics, it is notoriously difficult to identify driver events of malignant transformation. In this study, we show that murine and canine mesenchymal stem cells (MSCs) can be used to model spontaneous malignant transformation towards sarcomas with complex genomics. We show that these MSCs have an abnormal karyotype, many structural variants, and point mutations at whole genome sequencing analysis, and form sarcomas after injection into mice. Our cross-species analysis reveals that p53 loss is an early event in sarcomagenesis, and it was shown that MSCs with a knock-out in Trp53 transform earlier compared to wild-type MSCs. Our study points to the importance of p53 loss in the transformation process towards sarcomas with complex genomics.Sarcomas are rare mesenchymal tumors with a broad histological spectrum, but they can be divided into two groups based on molecular pathology: sarcomas with simple or complex genomics. Tumors with complex genomics can have aneuploidy and copy number gains and losses, which hampers the detection of early, initiating events in tumorigenesis. Often, no benign precursors are known, which is why good models are essential. The mesenchymal stem cell (MSC) is the presumed cell of origin of sarcoma. In this study, MSCs of murine and canine origin are used as a model to identify driver events for sarcomas with complex genomic alterations as they transform spontaneously after long-term culture. All transformed murine but not canine MSCs formed sarcomas after subcutaneous injection in mice. Using whole genome sequencing, spontaneously transformed murine and canine MSCs displayed a complex karyotype with aneuploidy, point mutations, structural variants, inter-chromosomal translocations, and copy number gains and losses. Cross-species analysis revealed that point mutations in Tp53/Trp53 are common in transformed murine and canine MSCs. Murine MSCs with a cre-recombinase induced deletion of exon 2-10 of Trp53 transformed earlier compared to wild-type murine MSCs, confirming the contribution of loss of p53 to spontaneous transformation. Our comparative approach using transformed murine and canine MSCs points to a crucial role for p53 loss in the formation of sarcomas with complex genomics.Molecular tumour pathology - and tumour geneticsMTG

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

The Yeast Pif1 Helicase Prevents Genomic Instability Caused by G-Quadruplex-Forming CEB1 Sequences In Vivo

In budding yeast, the Pif1 DNA helicase is involved in the maintenance of both nuclear and mitochondrial genomes, but its role in these processes is still poorly understood. Here, we provide evidence for a new Pif1 function by demonstrating that its absence promotes genetic instability of alleles of the G-rich human minisatellite CEB1 inserted in the Saccharomyces cerevisiae genome, but not of other tandem repeats. Inactivation of other DNA helicases, including Sgs1, had no effect on CEB1 stability. In vitro, we show that CEB1 repeats formed stable G-quadruplex (G4) secondary structures and the Pif1 protein unwinds these structures more efficiently than regular B-DNA. Finally, synthetic CEB1 arrays in which we mutated the potential G4-forming sequences were no longer destabilized in pif1Δ cells. Hence, we conclude that CEB1 instability in pif1Δ cells depends on the potential to form G-quadruplex structures, suggesting that Pif1 could play a role in the metabolism of G4-forming sequences

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation