Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome

Febrile infection‐related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new‐onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patient–parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes

Manipulable Objects Facilitate Cross-Modal Integration in Peripersonal Space

Previous studies have shown that tool use often modifies one's peripersonal space – i.e. the space directly surrounding our body. Given our profound experience with manipulable objects (e.g. a toothbrush, a comb or a teapot) in the present study we hypothesized that the observation of pictures representing manipulable objects would result in a remapping of peripersonal space as well. Subjects were required to report the location of vibrotactile stimuli delivered to the right hand, while ignoring visual distractors superimposed on pictures representing everyday objects. Pictures could represent objects that were of high manipulability (e.g. a cell phone), medium manipulability (e.g. a soap dispenser) and low manipulability (e.g. a computer screen). In the first experiment, when subjects attended to the action associated with the objects, a strong cross-modal congruency effect (CCE) was observed for pictures representing medium and high manipulability objects, reflected in faster reaction times if the vibrotactile stimulus and the visual distractor were in the same location, whereas no CCE was observed for low manipulability objects. This finding was replicated in a second experiment in which subjects attended to the visual properties of the objects. These findings suggest that the observation of manipulable objects facilitates cross-modal integration in peripersonal space

Trajectories of maternal symptoms of anxiety and depression. A 13-year longitudinal study of a population-based sample

<p>Abstract</p> <p>Background</p> <p>There is a lack of population-based studies of developmental trajectories following mothers throughout the whole child-rearing phase and there are few longitudinal studies focusing on both symptoms of depression and anxiety. The aim of the current study is to identify latent trajectory groups based on counts of symptoms of anxiety and depression among mothers throughout the child-rearing phase and the relations of the latent groups to maternal socio-demographic variables.</p> <p>Methods</p> <p>Data is from a prospective, longitudinal study of nearly 1000 families in Norway followed from when the index children were 18 months until they were 14.5 years old (the TOPP study). The study used latent profile analysis (LPA) to identify latent groups of mothers with distinct trajectories across time of symptom counts. Latent group differences on socio-demographic variables were tested with one-way ANOVAs, chi-square tests and exact tests.</p> <p>Results</p> <p>Six trajectories based on maternal scores from six waves of data collection of symptoms of anxiety and depression were identified; a 'No symptoms' group with mothers without symptoms; a 'Low' group with mothers reporting low symptom levels; a 'Moderate-low' group with mothers reporting moderately low symptom levels; a 'Moderate' group with mothers with moderate symptoms; a 'High-chronic' group with mothers with overall high symptom levels; and a 'Low-rising' group with mothers starting with a low symptom level that increased over time. The mothers in the High-chronic symptom group differed from the other mothers on several socio-demographic variables. They were significantly younger than the mothers in the Low group comprising the oldest mothers. The mothers in the High-chronic group had significantly lower education, were less likely to have paid work and were less likely to be living with a partner than the mothers in the other groups.</p> <p>Conclusions</p> <p>The study shows socio-demographic differences between mothers classified into six trajectory groups based on symptoms of anxiety and depression covering 13 years of the child-rearing period. Specific socio-demographic risk factors characterised mothers in the High-chronic symptom group. Identifying subgroups with enduring problems might inform more targeted preventive efforts.</p

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved

Insects as Stem Engineers: Interactions Mediated by the Twig-Girdler Oncideres albomarginata chamela Enhance Arthropod Diversity

Background: Ecosystem engineering may influence community structure and biodiversity by controlling the availability of resources and/or habitats used by other organisms. Insect herbivores may act as ecosystem engineers but there is still poor understanding of the role of these insects structuring arthropod communities. Methodology/Principal Findings: We evaluated the effect of ecosystem engineering by the stem-borer Oncideres albomarginata chamela on the arthropod community of a tropical dry forest for three consecutive years. The results showed that ecosystem engineering by O. albomarginata chamela had strong positive effects on the colonization, abundance, species richness and composition of the associated arthropod community, and it occurred mainly through the creation of a habitat with high availability of oviposition sites for secondary colonizers. These effects cascade upward to higher trophic levels. Overall, ecosystem engineering by O. albomarginata chamela was responsible for nearly 95 % of the abundance of secondary colonizers and 82 % of the species richness. Conclusions/Significance: Our results suggest that ecosystem engineering by O. albomarginata chamela is a keystone process structuring an arthropod community composed by xylovores, predators and parasitoids. This study is the first to empirically demonstrate the effect of the ecosystem engineering by stem-boring insects on important attributes o

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved

Clinical spectrum of STX1B-related epileptic disorders

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies

Clinical spectrum of STX1B-related epileptic disorders

Objective The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin- 1B, and establish genotype-phenotype correlations by identifying further disease related variants. Methods We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies