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See detailEnrichment of damaging missense variants in genes related with axonal guidance signalling in sporadic Meniere’s disease
Gallego-Martinez, Alvaro; Requena, Teresa; Roman-Naranjo, Pablo et al

in Journal of Medical Genetics (2019)

INTRODUCTION: Meniere's disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has ... [more ▼]

INTRODUCTION: Meniere's disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has been mostly described in sporadic cases, familial cases being around 10% of the observed individuals. It is associated with an accumulation of endolymph in the inner ear, but the molecular underpinnings remain largely unknown. The main molecular pathways showing higher differentially expressed genes in the supporting cells of the inner ear are related to cochlea-vestibular innervation, cell adhesion and leucocyte extravasation. In this study, our objective is to find a burden of rare variants in genes that interact with the main signalling pathways in supporting cells of the inner ear in patients with sporadic MD. METHODS: We designed a targeted-sequencing panel including genes related with the main molecular pathways in supporting cells and sequenced 860 Spanish patients with sporadic MD. Variants with minor allele frequencies <0.1 in the gene panel were compared with three independent reference datasets. Variants were classified as loss of function, missense and synonymous. Missense variants with a combined annotation-dependent depletion score of >20 were classified as damaging missense variants. RESULTS: We have observed a significant burden of damaging missense variants in few key genes, including the NTN4 gene, associated with axon guidance signalling pathways in patients with sporadic MD. We have also identified active subnetworks having an enrichment of rare variants in sporadic MD. CONCLUSION: The burden of missense variants in the NTN4 gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD. [less ▲]

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See detailAssessment of genetic variant burden in epilepsy-associated brain lesions
Niestroj, Lisa-Marie; May, Patrick UL; Artomov, Mykyta et al

in European Journal of Human Genetics (2019)

It is challenging to estimate genetic variant burden across different subtypes of epilepsy. Herein, we used a comparative approach to assess the diagnostic yield and genotype-phenotype correlations in the ... [more ▼]

It is challenging to estimate genetic variant burden across different subtypes of epilepsy. Herein, we used a comparative approach to assess the diagnostic yield and genotype-phenotype correlations in the four most common brain lesions in patients with drug-resistant focal epilepsy. Targeted sequencing analysis was performed for a panel of 161 genes with a mean coverage of > 400x. Lesional tissue was histopathologically reviewed and dissected from hippocampal sclerosis (n=15), ganglioglioma (n=16), dysembryoplastic neuroepithelial tumors (n=8) and ocal cortical dysplasia type II (n=15). Peripheral blood (n=12) or surgical tissue samples histopathologically classified as lesion-free (n=42) were available for comparison. Variants were classified as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics guidelines. Overall, we identified pathogenic and likely pathogenic variants in 25.9% of patients with a mean coverage of 383x. The highest number of pathogenic/ likely pathogenic variants was observed in patients with ganglioglioma (43.75%; all somatic) and dysembryoplastic neuroepithelial tumors (37.5%; all somatic), and in 20% of cases with focal cortical dysplasia type II (13.33% somatic, 6.67% germline). Pathogenic/likely pathogenic positive genes were disorder-specific and BRAF V600E the only recurrent pathogenic variant. This study represents a reference for diagnostic yield across the four most common lesion entities in patients with drug-resistant focal epilepsy. The observed large variability in variant burden by epileptic lesion type calls for whole exome sequencing of histopathologically well characterized tissue in a diagnostic setting and in research to discover novel disease-associated genes. [less ▲]

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See detailUltra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Feng, Yen-Chen Anne; Howrigan, Daniel P.; Abbott, Liam E. et al

in American Journal of Human Genetics (2019)

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared ... [more ▼]

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology. [less ▲]

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See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

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See detailInsights into protein structural, physicochemical, and functional consequences of missense variants in 1,330 disease-associated human genes 693259
Iqbal, Sumaiya; Jespersen, Jakob B.; Perez-Palma, Eduardo et al

E-print/Working paper (2019)

Inference of the structural and functional consequences of amino acid-altering missense variants is challenging and not yet scalable. Clinical and research applications of the colossal number of ... [more ▼]

Inference of the structural and functional consequences of amino acid-altering missense variants is challenging and not yet scalable. Clinical and research applications of the colossal number of identified missense variants is thus limited. Here we describe the aggregation and analysis of large-scale genomic variation and structural biology data for 1,330 disease-associated genes. Comparing the burden of 40 structural, physicochemical, and functional protein features of altered amino acids with 3-dimensional coordinates, we found 18 and 14 features that are associated with pathogenic and population missense variants, respectively. Separate analyses of variants from 24 protein functional classes revealed novel function-dependent vulnerable features. We then devised a quantitative spectrum, identifying variants with higher pathogenic variant-associated features. Finally, we developed a web resource (MISCAST; http://miscast.broadinstitute.org/) for interactive analysis of variants on linear and tertiary protein structures. The biological impact of missense variants available through the webtool will assist researchers in hypothesizing variant pathogenicity and disease trajectories. [less ▲]

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See detailSimple ClinVar:an interactive web server to explore and retrieve gene and disease variants 1 aggregated in ClinVar database
Pérez-Palma, Eduardo; Gramm, Marie; Nürnberg, Peter et al

in Nucleic Acids Research (2019)

Clinical genetic testing has exponentially expanded in recent years, leading to an overwhelming amount of patient variants with high variability in pathogenicity and heterogeneous phenotypes. A large part ... [more ▼]

Clinical genetic testing has exponentially expanded in recent years, leading to an overwhelming amount of patient variants with high variability in pathogenicity and heterogeneous phenotypes. A large part of the variant level data are comprehensively aggregated in public databases such as ClinVar. However, the ability to explore this rich resource and answer general questions such as “How many genes inside ClinVar are associated with a specific disease? or “In which part of the protein are patient variants located?” is limited and requires advanced bioinformatics processing. Here, we present Simple ClinVar (http://simple-clinvar.broadinstitute.org/) a web- server application that is able to provide variant, gene, and disease level summary statistics based on the entire ClinVar database in a dynamic and user-friendly web-interface. Overall, our web application is able to interactively answer basic questions regarding genetic variation and its known relationships to disease. By typing a disease term of interest, t he user can identify in seconds the genes and phenotypes most frequently reported to ClinVar. Subsets of variants can then be further explored, filtered, or mapped and visualized in the corresponding protein sequences. Our website will follow ClinVar monthly releases and provide easy access to rich ClinVar resources to a broader audience including basic and clinical scientists. [less ▲]

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See detailIdentification of pathogenic variant enriched regions across genes and gene families
Pérez-Palma, Eduardo; May, Patrick UL; Iqbal, Sumaiya et al

E-print/Working paper (2019)

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to ... [more ▼]

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 65,034 missense variants from patients. With this gene family approach, we identified 398 regions enriched for patient variants spanning 33,887 amino acids in 1,058 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,167 amino acids and 180 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed a 5.56-fold enrichment of patient variants in our identified regions (95% C.I. =2.76-Inf, p-value = 6.66×10−8). Using an independent ClinVar variant set, we found missense variants inside the identified regions are 111-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 111.48, 95% C.I = 68.09-195.58, p-value < 2.2e−16). All patient variant enriched regions identified (PERs) are available online through a user-friendly platform for interactive data mining, visualization and download at http://per.broadinstitute.org. In summary, our gene family burden analysis approach identified novel patient variant enriched regions in protein sequences. This annotation can empower variant interpretation. [less ▲]

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See detailA Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
Helbig, Ingo; Lopez-Hernandez, Tania; Shor, Oded et al

in American journal of human genetics (2019)

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of ... [more ▼]

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the mu-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2mu conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy. [less ▲]

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See detailVariant Score Ranker - a web application for intuitive missense variant prioritization
Du, Juanjiangmeng; Sudarsanam, Monica; Pérez-Palma, Eduardo et al

in Bioinformatics (2019)

The correct classification of missense variants as benign or pathogenic remains challenging. Pathogenic variants are expected to have higher deleterious prediction scores than benign variants in the same ... [more ▼]

The correct classification of missense variants as benign or pathogenic remains challenging. Pathogenic variants are expected to have higher deleterious prediction scores than benign variants in the same gene. However, most of the existing variant annotation tools do not reference the score range of benign population variants on gene level. Here, we present a web-application, Variant Score Ranker, which enables users to rapidly annotate variants and perform gene-specific variant score ranking on the population level. We also provide an intuitive example of how gene- and population-calibrated variant ranking scores can improve epilepsy variant prioritization. [less ▲]

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See detailIntestinal-Cell Kinase and Juvenile Myoclonic Epilepsy.
Lerche, Holger; Berkovic, Sam F.; Lowenstein, Daniel H. et al

in New England Journal of Medicine (2019), 380(16), 24

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including ... [more ▼]

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including juvenile myoclonic epilepsy: We attempted replication by rechecking for enrichment of ICK variants in two previously published analyses of mainly familial cases of genetic generalized epilepsy, which included a total of 1149 cases of genetic generalized epilepsy and 5911 ethnically matched controls. We analyzed the burden of single-gene rare variants with the use of whole exome sequencing data, applying population stratification and both sample and variant quality control. We found no evidence of an enrichment of ICK variants in genetic generalized epilepsies or juvenile myoclonic epilepsy. Specifically, we did not detect a nonsynonymous variant in 357 persons with juvenile myoclonic epilepsy at a minor allele frequency at or below 0.1%. Although we cannot exclude the possibility that ICK variants may be population-specific risk factors for juvenile myoclonic epilepsy, the lack of validation in our cohorts does not support a true disease association but rather suggests that the authors’ results may be due to chance, possibly owing to methodologic issues (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). [less ▲]

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See detailHemap: An nteractive online resource for characterizing molecular phenotypes across hematologic malignancies
Pölönen, Petri; Mehtonen, Juha; Lin, Jake et al

in Cancer Research (2019)

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease contexts for new ... [more ▼]

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease contexts for new therapeutic approaches. We analyzed 9,544 transcriptomes from over 30 hematologic malignancies, normal blood cell types and cell lines, and show that the disease types can be stratified in a data-driven manner. We utilized the obtained molecular clustering for discovery of cluster-specific pathway activity, new biomarkers and in silico drug target prioritization through integration with drug target databases. Using known vulnerabilities and available drug screens in benchmarking, we highlight the importance of integrating the molecular phenotype context and drug target expression for in silico prediction of drug responsiveness. Our analysis implicates BCL2 expression level as important indicator of venetoclax responsiveness and provides a rationale for its targeting in specific leukemia subtypes and multiple myeloma, links several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7 and EZH1) with CLL, and supports CDK6 as disease-specific target in AML. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our freely available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies. [less ▲]

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See detailFunctional Interpretation of Single Amino Acid Substitutions in 1,330 Disease-Associated Genes
Iqbal, Sumaiya; Jespersen, Jakob Berg; Perez-Palma, Eduardo et al

in Biophysical Journal (2019, February 15), 116(3), 420-421

Elucidating molecular consequences of amino-acid-altering missense variants at scale is challenging. In this work, we explored whether features derived from three-dimensional (3D) protein structures can ... [more ▼]

Elucidating molecular consequences of amino-acid-altering missense variants at scale is challenging. In this work, we explored whether features derived from three-dimensional (3D) protein structures can characterize patient missense variants across different protein classes with similar molecular level activities. The identified disease-associated features can advance our understanding of how a single amino acid substitution can lead to the etiology of monogenic disorders. For 1,330 disease-associated genes (>80%, 1,077/1,330 implicated in Mendelian disorders), we collected missense variants from the general population (gnomAD database, N=164,915) and patients (ClinVar and HGMD databases, N=32,923). We in silico mapped the variant positions onto >14k human protein 3D structures. We annotated the protein positions of variants with 40 structural, physiochemical, and functional features. We then grouped the genes into 24 protein classes based on their molecular functions and performed statistical association analyses with the features of population and patient variants. We identified 18 (out of 40) features that are associated with patient variants in general. Specifically, patient variants are less exposed to solvent (p<1.0e-100), enriched on b-sheets (p<2.37e-39), frequently mutate aromatic residues (p<1.0e-100), occur in ligand binding sites (p<1.0e-100) and are spatially close to phosphorylation sites (p<1.0e-100). We also observed differential protein-class-specific features. For three protein classes (signaling molecules, proteases and hydrolases), patient variants significantly perturb the disulfide bonds (p<1.0e-100). Only in immunity proteins, patient variants are enriched in flexible coils (p<1.65e-06). Kinases and cell junction proteins exhibit enrichment of patient variants around SUMOylation (p<1.0e-100) and methylation sites (p<9.29e-11), respectively. In summary, we studied shared and unique features associated with patient variants on protein structure across 24 protein classes, providing novel mechanistic insights. We generated an online resource that contains amino-acid-wise feature annotation-track for 1,330 genes, summarizes the patient-variant-associated features on residue level, and can guide variant interpretation. [less ▲]

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See detailBiallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Siekierska, Aleksandra; Stamberger, Hannah; Deconinck, Tine et al

in Nature Communications (2019), 10(1), 708

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often ... [more ▼]

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies. [less ▲]

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See detailClinical spectrum of STX1B-related epileptic disorders
Wolking, Stefan; May, Patrick UL; Mei, Davide et al

in Neurology (2019), 92

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by ... [more ▼]

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to 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 fifteen new variants in STX1B which are distributed across the whole gene. We discerned four different phenotypic groups across the newly identified and previously published patients (49 in 23 families): 1) Six 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 neurological deficits; 2) two patients of genetic generalized epilepsy without febrile seizures and cognitive deficits; 3) thirteen patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; 4) two patients with focal epilepsy. Nonsense mutations were found more often 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 ILAE classification. Variants in STX1B are protean, and able to contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. [less ▲]

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See detailSpectrum of GABAA receptor variants in epilepsy
Maljevic, Snezana; Møller, Rikke S.; Reid, Christopher A. et al

in Current Opinion in Neurology (2019)

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of ... [more ▼]

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. Recent findings: Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epileptic encephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epileptic encephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. Summary: Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs. [less ▲]

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See detailPredicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
Heyne, Henrike O.; Baez-Nieto, David; Iqbal, Sumaiya et al

E-print/Working paper (2019)

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is ... [more ▼]

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice. [less ▲]

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See detailWeb-based QTL linkage analysis and bulk segregant analysis of yeast sequencing data
Zhang, Zhi; Jung, Paul; Groues, Valentin UL et al

in GigaScience (2019), 8(6), 060

Quantitative Trait Loci (QTL) mapping using bulk segregants is an effective approach for identifying genetic variants associated with phenotypes of interest in model organisms. By exploiting next ... [more ▼]

Quantitative Trait Loci (QTL) mapping using bulk segregants is an effective approach for identifying genetic variants associated with phenotypes of interest in model organisms. By exploiting next-generation sequencing technology, the QTL mapping accuracy can be improved significantly, providing a valuable means to annotate new genetic variants. However, setting up a comprehensive analysis framework for this purpose is a time-consuming and error prone task, posing many challenges for scientists with limited experience in this domain. Findings: Here, we present BSA4Yeast, a comprehensive web-application for QTL mapping via bulk segregant analysis of yeast sequencing data. The software provides an automated and efficiency-optimized data processing, up-to-date functional annotations, and an interactive web-interface to explore identified QTLs. Conclusion: BSA4Yeast enables researchers to identify plausible candidate genes in QTL regions efficiently in order to validate their genetic variations experimentally as causative for a phenotype of interest. BSA4Yeast is freely available at https://bsa4yeast.lcsb.uni.lu. [less ▲]

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See detailGuideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies
Niestroj, Lisa-Marie; Du, Juanjiangmeng; Nothnagel, Michael et al

in Epilepsia (2018)

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and Focal Cortical Dysplasia (FCD) or low-grade glio-neuronal tumors has fostered large-scale ... [more ▼]

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and Focal Cortical Dysplasia (FCD) or low-grade glio-neuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germline and somatic variants remains difficult. Here, we present a state of the art evaluation of reported genes and variants associated with epileptic brain lesions. Methods: We critically re-evaluated the pathogenicity for all neuropathology-associated variants reported to date in PubMed and ClinVar databases including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. Results: Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven out of 11 genes to be likely disease-associated according to the reported a disease mechanism, while 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance (VUS), 37 (36.6%) as being likely pathogenic (LP) and 3 (3%) as being pathogenic (P). Significance: We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging and application of current ACMG guidelines is recommended for interpretation and prediction. [less ▲]

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See detailMajor changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift
Gutbier, Simon; May, Patrick UL; Berthelot, Sylvie et al

in Archives of Toxicology (2018)

Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored ... [more ▼]

Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyridinium (MPP+) were observed. Whole-genome sequencing was performed to identify underlying genetic differences. While both SP had normal chromosome structures, they displayed about 70 differences on the level of amino acid changing events. Some of these differences were confirmed biochemically, but none offered a direct explanation for the altered toxicant sensitivity pattern. As second approach, markers known to be relevant for the intended use of the cells were specifically tested. The “ATCC” cells rapidly down-regulated the dopamine-transporter and tyrosine-hydroxylase after differentiation, while “UKN” cells maintained functional levels. As the respective genes were not altered themselves, we conclude that polygenic complex upstream changes can have drastic effects on biochemical features and toxicological responses of relatively similar SP of cells. [less ▲]

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