@article{691, abstract = {Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. Objective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families. Methods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease. Results: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold. Conclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.}, author = {Marin Valencia, Isaac and Novarino, Gaia and Johansen, Anide and Rosti, Başak and Issa, Mahmoud and Musaev, Damir and Bhat, Gifty and Scott, Eric and Silhavy, Jennifer and Stanley, Valentina and Rosti, Rasim and Gleeson, Jeremy and Imam, Farhad and Zaki, Maha and Gleeson, Joseph}, issn = {0022-2593}, journal = {Journal of Medical Genetics}, number = {1}, pages = {48 -- 54}, publisher = {BMJ Publishing Group}, title = {{A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features}}, doi = {10.1136/jmedgenet-2017-104627}, volume = {55}, year = {2018}, } @phdthesis{395, abstract = {Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. }, author = {Tarlungeanu, Dora-Clara}, issn = {2663-337X}, pages = {88}, publisher = {Institute of Science and Technology Austria}, title = {{The branched chain amino acids in autism spectrum disorders }}, doi = {10.15479/AT:ISTA:th_992}, year = {2018}, } @article{3, abstract = {SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder.}, author = {Deliu, Elena and Arecco, Niccoló and Morandell, Jasmin and Dotter, Christoph and Contreras, Ximena and Girardot, Charles and Käsper, Eva and Kozlova, Alena and Kishi, Kasumi and Chiaradia, Ilaria and Noh, Kyung and Novarino, Gaia}, journal = {Nature Neuroscience}, number = {12}, pages = {1717 -- 1727}, publisher = {Nature Publishing Group}, title = {{Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition}}, doi = {10.1038/s41593-018-0266-2}, volume = {21}, year = {2018}, } @article{540, abstract = {RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics. A subsequent mass-spectrometric analysis of L protein pulldowns from infected human cells revealed a comprehensive network of interacting host proteins. The obtained LCMV L protein interactome was bioinformatically integrated with known host protein interactors of RdRps from other RNA viruses, emphasizing interconnected modules of human proteins. Functional characterization of selected interactors highlighted proviral (DDX3X) as well as antiviral (NKRF, TRIM21) host factors. To corroborate these findings, we infected Trim21-/-mice with LCMV and found impaired virus control in chronic infection. These results provide insights into the complex interactions of the arenavirus LCMV and other viral RdRps with the host proteome and contribute to a better molecular understanding of how chronic viruses interact with their host.}, author = {Khamina, Kseniya and Lercher, Alexander and Caldera, Michael and Schliehe, Christopher and Vilagos, Bojan and Sahin, Mehmet and Kosack, Lindsay and Bhattacharya, Anannya and Májek, Peter and Stukalov, Alexey and Sacco, Roberto and James, Leo and Pinschewer, Daniel and Bennett, Keiryn and Menche, Jörg and Bergthaler, Andreas}, issn = {15537366}, journal = {PLoS Pathogens}, number = {12}, publisher = {Public Library of Science}, title = {{Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein}}, doi = {10.1371/journal.ppat.1006758}, volume = {13}, year = {2017}, } @inbook{623, abstract = {Genetic factors might be largely responsible for the development of autism spectrum disorder (ASD) that alone or in combination with specific environmental risk factors trigger the pathology. Multiple mutations identified in ASD patients that impair synaptic function in the central nervous system are well studied in animal models. How these mutations might interact with other risk factors is not fully understood though. Additionally, how systems outside of the brain are altered in the context of ASD is an emerging area of research. Extracerebral influences on the physiology could begin in utero and contribute to changes in the brain and in the development of other body systems and further lead to epigenetic changes. Therefore, multiple recent studies have aimed at elucidating the role of gene-environment interactions in ASD. Here we provide an overview on the extracerebral systems that might play an important associative role in ASD and review evidence regarding the potential roles of inflammation, trace metals, metabolism, genetic susceptibility, enteric nervous system function and the microbiota of the gastrointestinal (GI) tract on the development of endophenotypes in animal models of ASD. By influencing environmental conditions, it might be possible to reduce or limit the severity of ASD pathology.}, author = {Hill Yardin, Elisa and Mckeown, Sonja and Novarino, Gaia and Grabrucker, Andreas}, booktitle = {Translational Anatomy and Cell Biology of Autism Spectrum Disorder}, editor = {Schmeisser, Michael and Boekers, Tobias}, isbn = {978-3-319-52496-2}, issn = {03015556}, pages = {159 -- 187}, publisher = {Springer}, title = {{Extracerebral dysfunction in animal models of autism spectrum disorder}}, doi = {10.1007/978-3-319-52498-6_9}, volume = {224}, year = {2017}, } @inbook{634, abstract = {As autism spectrum disorder (ASD) is largely regarded as a neurodevelopmental condition, long-time consensus was that its hallmark features are irreversible. However, several studies from recent years using defined mouse models of ASD have provided clear evidence that in mice neurobiological and behavioural alterations can be ameliorated or even reversed by genetic restoration or pharmacological treatment either before or after symptom onset. Here, we review findings on genetic and pharmacological reversibility of phenotypes in mouse models of ASD. Our review should give a comprehensive overview on both aspects and encourage future studies to better understand the underlying molecular mechanisms that might be translatable from animals to humans.}, author = {Schroeder, Jan and Deliu, Elena and Novarino, Gaia and Schmeisser, Michael}, booktitle = {Translational Anatomy and Cell Biology of Autism Spectrum Disorder}, editor = {Schmeisser, Michael and Boekers, Tobias}, pages = {189 -- 211}, publisher = {Springer}, title = {{Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder}}, doi = {10.1007/978-3-319-52498-6_10}, volume = {224}, year = {2017}, } @article{656, abstract = {Human neurons transplanted into a mouse model for Alzheimer’s disease show human-specific vulnerability to β-amyloid plaques and may help to identify new therapeutic targets.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {381}, publisher = {American Association for the Advancement of Science}, title = {{Modeling Alzheimer's disease in mice with human neurons}}, doi = {10.1126/scitranslmed.aam9867}, volume = {9}, year = {2017}, } @article{667, abstract = {Perinatal exposure to penicillin may result in longlasting gut and behavioral changes.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {387}, publisher = {American Association for the Advancement of Science}, title = {{The antisocial side of antibiotics}}, doi = {10.1126/scitranslmed.aan2786}, volume = {9}, year = {2017}, } @article{689, abstract = {Rett syndrome modeling in monkey mirrors the human disorder.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {393}, publisher = {American Association for the Advancement of Science}, title = {{Rett syndrome modeling goes simian}}, doi = {10.1126/scitranslmed.aan8196}, volume = {9}, year = {2017}, } @article{702, abstract = {Leading autism-associated mutation in mouse partially mimics human disorder. }, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {399}, pages = {eaao0972}, publisher = {American Association for the Advancement of Science}, title = {{The riddle of CHD8 haploinsufficiency in autism spectrum disorder}}, doi = {10.1126/scitranslmed.aao0972}, volume = {9}, year = {2017}, } @article{713, abstract = {To determine the dynamics of allelic-specific expression during mouse development, we analyzed RNA-seq data from 23 F1 tissues from different developmental stages, including 19 female tissues allowing X chromosome inactivation (XCI) escapers to also be detected. We demonstrate that allelic expression arising from genetic or epigenetic differences is highly tissue-specific. We find that tissue-specific strain-biased gene expression may be regulated by tissue-specific enhancers or by post-transcriptional differences in stability between the alleles. We also find that escape from X-inactivation is tissue-specific, with leg muscle showing an unexpectedly high rate of XCI escapers. By surveying a range of tissues during development, and performing extensive validation, we are able to provide a high confidence list of mouse imprinted genes including 18 novel genes. This shows that cluster size varies dynamically during development and can be substantially larger than previously thought, with the Igf2r cluster extending over 10 Mb in placenta.}, author = {Andergassen, Daniel and Dotter, Christoph and Wenzel, Dyniel and Sigl, Verena and Bammer, Philipp and Muckenhuber, Markus and Mayer, Daniela and Kulinski, Tomasz and Theussl, Hans and Penninger, Josef and Bock, Christoph and Barlow, Denise and Pauler, Florian and Hudson, Quanah}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Mapping the mouse Allelome reveals tissue specific regulation of allelic expression}}, doi = {10.7554/eLife.25125}, volume = {6}, year = {2017}, } @article{714, abstract = {Background HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. Methods We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons. Results We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+. Conclusion We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients.}, author = {Brailoiu, Gabriela and Deliu, Elena and Barr, Jeffrey and Console Bram, Linda and Ciuciu, Alexandra and Abood, Mary and Unterwald, Ellen and Brǎiloiu, Eugen}, issn = {03768716}, journal = {Drug and Alcohol Dependence}, pages = {7 -- 14}, publisher = {Elsevier}, title = {{HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens}}, doi = {10.1016/j.drugalcdep.2017.04.015}, volume = {178}, year = {2017}, } @article{715, abstract = {D-cycloserine ameliorates breathing abnormalities and survival rate in a mouse model of Rett syndrome.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {405}, publisher = {American Association for the Advancement of Science}, title = {{More excitation for Rett syndrome}}, doi = {10.1126/scitranslmed.aao4218}, volume = {9}, year = {2017}, } @article{731, abstract = {Genetic variations in the oxytocin receptor gene affect patients with ASD and ADHD differently.}, author = {Novarino, Gaia}, issn = {19466234}, journal = {Science Translational Medicine}, number = {411}, publisher = {American Association for the Advancement of Science}, title = {{The science of love in ASD and ADHD}}, doi = {10.1126/scitranslmed.aap8168}, volume = {9}, year = {2017}, } @article{1228, abstract = {Since 2006, reprogrammed cells have increasingly been used as a biomedical research technique in addition to neuro-psychiatric methods. These rapidly evolving techniques allow for the generation of neuronal sub-populations, and have sparked interest not only in monogenetic neuro-psychiatric diseases, but also in poly-genetic and poly-aetiological disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). This review provides a summary of 19 publications on reprogrammed adult somatic cells derived from patients with SCZ, and five publications using this technique in patients with BPD. As both disorders are complex and heterogeneous, there is a plurality of hypotheses to be tested in vitro. In SCZ, data on alterations of dopaminergic transmission in vitro are sparse, despite the great explanatory power of the so-called DA hypothesis of SCZ. Some findings correspond to perturbations of cell energy metabolism, and observations in reprogrammed cells suggest neuro-developmental alterations. Some studies also report on the efficacy of medicinal compounds to revert alterations observed in cellular models. However, due to the paucity of replication studies, no comprehensive conclusions can be drawn from studies using reprogrammed cells at the present time. In the future, findings from cell culture methods need to be integrated with clinical, epidemiological, pharmacological and imaging data in order to generate a more comprehensive picture of SCZ and BPD.}, author = {Sauerzopf, Ulrich and Sacco, Roberto and Novarino, Gaia and Niello, Marco and Weidenauer, Ana and Praschak Rieder, Nicole and Sitte, Harald and Willeit, Matthaeus}, journal = {European Journal of Neuroscience}, number = {1}, pages = {45 -- 57}, publisher = {Wiley-Blackwell}, title = {{Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence}}, doi = {10.1111/ejn.13418}, volume = {45}, year = {2017}, } @article{747, abstract = {Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regulation. BK produced a dose-dependent increase in cytosolic Ca2+ concentration. Pretreatment with HOE140, a B2 receptor antagonist, but not with R715, a B1 receptor antagonist, abolished the response to BK. A selective B2 receptor agonist, but not a B1 receptor agonist, elicited an increase in cytosolic Ca2+ similarly to BK. Inhibition of N-type voltage-gated Ca2+ channels with ω-conotoxin GVIA had no effect on the Ca2+ signal produced by BK, while pretreatment with ω-conotoxin MVIIC, a blocker of P/Q-type of Ca2+ channels, significantly diminished the effect of BK. Pretreatment with xestospongin C and 2-aminoethoxydiphenyl borate, antagonists of inositol 1,4,5-trisphosphate receptors, abolished the response to BK. Inhibition of ryanodine receptors reduced the BK-induced Ca2+ increase, while disruption of lysosomal Ca2+ stores with bafilomycin A1 did not affect the response. BK produced a dose-dependent depolarization of nucleus ambiguus neurons, which was prevented by the B2 receptor antagonist. In vivo studies indicate that microinjection of BK into nucleus ambiguus elicited bradycardia in conscious rats via B2 receptors. In summary, in cardiac vagal neurons of nucleus ambiguus, BK activates B2 receptors promoting Ca2+ influx and Ca2+ release from endoplasmic reticulum, and membrane depolarization; these effects are translated in vivo by bradycardia.}, author = {Brǎiloiu, Eugen and Mcguire, Matthew and Shuler, Shadaria and Deliu, Elena and Barr, Jeffrey and Abood, Mary and Brailoiu, Gabriela}, issn = {03064522}, journal = {Neuroscience}, pages = {23 -- 32}, publisher = {Elsevier}, title = {{Modulation of cardiac vagal tone by bradykinin acting on nucleus ambiguus}}, doi = {10.1016/j.neuroscience.2017.09.034}, volume = {365}, year = {2017}, } @article{1240, abstract = {Background: Long non-coding RNAs (lncRNAs) are increasingly implicated as gene regulators and may ultimately be more numerous than protein-coding genes in the human genome. Despite large numbers of reported lncRNAs, reference annotations are likely incomplete due to their lower and tighter tissue-specific expression compared to mRNAs. An unexplored factor potentially confounding lncRNA identification is inter-individual expression variability. Here, we characterize lncRNA natural expression variability in human primary granulocytes. Results: We annotate granulocyte lncRNAs and mRNAs in RNA-seq data from 10 healthy individuals, identifying multiple lncRNAs absent from reference annotations, and use this to investigate three known features (higher tissue-specificity, lower expression, and reduced splicing efficiency) of lncRNAs relative to mRNAs. Expression variability was examined in seven individuals sampled three times at 1- or more than 1-month intervals. We show that lncRNAs display significantly more inter-individual expression variability compared to mRNAs. We confirm this finding in two independent human datasets by analyzing multiple tissues from the GTEx project and lymphoblastoid cell lines from the GEUVADIS project. Using the latter dataset we also show that including more human donors into the transcriptome annotation pipeline allows identification of an increasing number of lncRNAs, but minimally affects mRNA gene number. Conclusions: A comprehensive annotation of lncRNAs is known to require an approach that is sensitive to low and tight tissue-specific expression. Here we show that increased inter-individual expression variability is an additional general lncRNA feature to consider when creating a comprehensive annotation of human lncRNAs or proposing their use as prognostic or disease markers.}, author = {Kornienko, Aleksandra and Dotter, Christoph and Guenzl, Philipp and Gisslinger, Heinz and Gisslinger, Bettina and Cleary, Ciara and Kralovics, Robert and Pauler, Florian and Barlow, Denise}, journal = {Genome Biology}, number = {1}, publisher = {BioMed Central}, title = {{Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans}}, doi = {10.1186/s13059-016-0873-8}, volume = {17}, year = {2016}, } @article{1183, abstract = {Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.}, author = {Tarlungeanu, Dora-Clara and Deliu, Elena and Dotter, Christoph and Kara, Majdi and Janiesch, Philipp and Scalise, Mariafrancesca and Galluccio, Michele and Tesulov, Mateja and Morelli, Emanuela and Sönmez, Fatma and Bilgüvar, Kaya and Ohgaki, Ryuichi and Kanai, Yoshikatsu and Johansen, Anide and Esharif, Seham and Ben Omran, Tawfeg and Topcu, Meral and Schlessinger, Avner and Indiveri, Cesare and Duncan, Kent and Caglayan, Ahmet and Günel, Murat and Gleeson, Joseph and Novarino, Gaia}, journal = {Cell}, number = {6}, pages = {1481 -- 1494}, publisher = {Cell Press}, title = {{Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder}}, doi = {10.1016/j.cell.2016.11.013}, volume = {167}, year = {2016}, } @article{1497, abstract = {Detecting allelic biases from high-throughput sequencing data requires an approach that maximises sensitivity while minimizing false positives. Here, we present Allelome.PRO, an automated user-friendly bioinformatics pipeline, which uses high-throughput sequencing data from reciprocal crosses of two genetically distinct mouse strains to detect allele-specific expression and chromatin modifications. Allelome.PRO extends approaches used in previous studies that exclusively analyzed imprinted expression to give a complete picture of the ‘allelome’ by automatically categorising the allelic expression of all genes in a given cell type into imprinted, strain-biased, biallelic or non-informative. Allelome.PRO offers increased sensitivity to analyze lowly expressed transcripts, together with a robust false discovery rate empirically calculated from variation in the sequencing data. We used RNA-seq data from mouse embryonic fibroblasts from F1 reciprocal crosses to determine a biologically relevant allelic ratio cutoff, and define for the first time an entire allelome. Furthermore, we show that Allelome.PRO detects differential enrichment of H3K4me3 over promoters from ChIP-seq data validating the RNA-seq results. This approach can be easily extended to analyze histone marks of active enhancers, or transcription factor binding sites and therefore provides a powerful tool to identify candidate cis regulatory elements genome wide.}, author = {Andergassen, Daniel and Dotter, Christoph and Kulinski, Tomasz and Guenzl, Philipp and Bammer, Philipp and Barlow, Denise and Pauler, Florian and Hudson, Quanah}, journal = {Nucleic Acids Research}, number = {21}, publisher = {Oxford University Press}, title = {{Allelome.PRO, a pipeline to define allele-specific genomic features from high-throughput sequencing data}}, doi = {10.1093/nar/gkv727}, volume = {43}, year = {2015}, } @article{1789, abstract = {Intellectual disability (ID) has an estimated prevalence of 2-3%. Due to its extreme heterogeneity, the genetic basis of ID remains elusive in many cases. Recently, whole exome sequencing (WES) studies revealed that a large proportion of sporadic cases are caused by de novo gene variants. To identify further genes involved in ID, we performed WES in 250 patients with unexplained ID and their unaffected parents and included exomes of 51 previously sequenced child-parents trios in the analysis. Exome analysis revealed de novo intragenic variants in SET domain-containing 5 (SETD5) in two patients. One patient carried a nonsense variant, and the other an 81 bp deletion located across a splice-donor site. Chromosomal microarray diagnostics further identified four de novo non-recurrent microdeletions encompassing SETD5. CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions. In silico domain prediction of SETD5, a predicted SET domain-containing histone methyltransferase (HMT), substantiated the presence of a SET domain and identified a novel putative PHD domain, strengthening a functional link to well-known histone-modifying ID genes. All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype. The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID.}, author = {Kuechler, Alma and Zink, Alexander and Wieland, Thomas and Lüdecke, Hermann and Cremer, Kirsten and Salviati, Leonardo and Magini, Pamela and Najafi, Kimia and Zweier, Christiane and Czeschik, Johanna and Aretz, Stefan and Endele, Sabine and Tamburrino, Federica and Pinato, Claudia and Clementi, Maurizio and Gundlach, Jasmin and Maylahn, Carina and Mazzanti, Laura and Wohlleber, Eva and Schwarzmayr, Thomas and Kariminejad, Roxana and Schlessinger, Avner and Wieczorek, Dagmar and Strom, Tim and Novarino, Gaia and Engels, Hartmut}, journal = {European Journal of Human Genetics}, number = {6}, pages = {753 -- 760}, publisher = {Nature Publishing Group}, title = {{Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome}}, doi = {10.1038/ejhg.2014.165}, volume = {23}, year = {2015}, } @article{1916, abstract = {Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.}, author = {Novarino, Gaia and Fenstermaker, Ali and Zaki, Maha and Hofree, Matan and Silhavy, Jennifer and Heiberg, Andrew and Abdellateef, Mostafa and Rosti, Başak and Scott, Eric and Mansour, Lobna and Masri, Amira and Kayserili, Hülya and Al Aama, Jumana and Abdel Salam, Ghada and Karminejad, Ariana and Kara, Majdi and Kara, Bülent and Bozorgmehri, Bita and Ben Omran, Tawfeg and Mojahedi, Faezeh and Mahmoud, Iman and Bouslam, Naïma and Bouhouche, Ahmed and Benomar, Ali and Hanein, Sylvain and Raymond, Laure and Forlani, Sylvie and Mascaro, Massimo and Selim, Laila and Shehata, Nabil and Al Allawi, Nasir and Bindu, Parayil and Azam, Matloob and Günel, Murat and Caglayan, Ahmet and Bilgüvar, Kaya and Tolun, Aslihan and Issa, Mahmoud and Schroth, Jana and Spencer, Emily and Rosti, Rasim and Akizu, Naiara and Vaux, Keith and Johansen, Anide and Koh, Alice and Megahed, Hisham and Dürr, Alexandra and Brice, Alexis and Stévanin, Giovanni and Gabriel, Stacy and Ideker, Trey and Gleeson, Joseph}, journal = {Science}, number = {6170}, pages = {506 -- 511}, publisher = {American Association for the Advancement of Science}, title = {{Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders}}, doi = {10.1126/science.1247363}, volume = {343}, year = {2014}, }