References of "May, Patrick 50002348"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailComprehensive characterization of amino acidpositions in protein structures reveals moleculareffect of missense variants
iqbal, Sumaiya; Perez-Palma, Eduardo; Jespersen, Jakob B. et al

in Proceedings of the National Academy of Sciences of the United States of America (2020)

Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid ... [more ▼]

Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid-substituting missense variations on protein structure and function being especially challenging. Here we characterize the three-dimensional (3D) amino acid positions affected in pathogenic and population variants from 1,330 disease-associated genes using over 14,000 experimentally solved human protein structures. By measuring the statistical burden of variations (i.e., point mutations) from all genes on 40 3D protein features, accounting for the structural, chemical, and functional context of the variations’ positions, we identify features that are generally associated with pathogenic and population missense variants. We then perform the same amino acid-level analysis individually for 24 protein functional classes, which reveals unique characteristics of the positions of the altered amino acids: We observe up to 46% divergence of the class-specific features from the general characteristics obtained by the analysis on all genes, which is consistent with the structural diversity of essential regions across different protein classes. We demonstrate that the function-specific 3D features of the variants match the readouts of mutagenesis experiments for BRCA1 and PTEN, and positively correlate with an independent set of clinically interpreted pathogenic and benign missense variants. Finally, we make our results available through a web server to foster accessibility and downstream research. Our findings represent a crucial step toward translational genetics, from highlighting the impact of mutations on protein structure to rationalizing the variants’ pathogenicity in terms of the perturbed molecular mechanisms. [less ▲]

Detailed reference viewed: 21 (0 UL)
Full Text
Peer Reviewed
See detailPatient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
Golebiewska, Anna UL; Hau, Ann-Christin; Oudin, Anaïs et al

in Acta neuropathologica (2020)

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique ... [more ▼]

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology. [less ▲]

Detailed reference viewed: 81 (2 UL)
Full Text
Peer Reviewed
See detailNon-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease
Acharya, Shubhra; Salgado-Somoza, Antonio; Stefanizzi, Francesca Maria et al

in International Journal of Molecular Sciences (2020), 21(18), 6513

Parkinson’s disease (PD) is a complex and heterogeneous disorder involving multiple genetic and environmental influences. Although a wide range of PD risk factors and clinical markers for the symptomatic ... [more ▼]

Parkinson’s disease (PD) is a complex and heterogeneous disorder involving multiple genetic and environmental influences. Although a wide range of PD risk factors and clinical markers for the symptomatic motor stage of the disease have been identified, there are still no reliable biomarkers available for the early pre-motor phase of PD and for predicting disease progression. High-throughput RNA-based biomarker profiling and modeling may provide a means to exploit the joint information content from a multitude of markers to derive diagnostic and prognostic signatures. In the field of PD biomarker research, currently, no clinically validated RNA-based biomarker models are available, but previous studies reported several significantly disease-associated changes in RNA abundances and activities in multiple human tissues and body fluids. Here, we review the current knowledge of the regulation and function of non-coding RNAs in PD, focusing on microRNAs, long non-coding RNAs, and circular RNAs. Since there is growing evidence for functional interactions between the heart and the brain, we discuss the benefits of studying the role of non-coding RNAs in organ interactions when deciphering the complex regulatory networks involved in PD progression. We finally review important concepts of harmonization and curation of high throughput datasets, and we discuss the potential of systems biomedicine to derive and evaluate RNA biomarker signatures from high-throughput expression data. [less ▲]

Detailed reference viewed: 75 (1 UL)
Full Text
Peer Reviewed
See detailPredicting functional effects of missense variants in voltage-gated sodium and calcium channels
Heyne, Henrike O.; Baez-Nieto, David; Iqbal, Sumaiya et al

in Science Translational Medicine (2020), 12(556), 6848

Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases ... [more ▼]

Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) 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) that often corresponds not only 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. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (n = 518) and GOF (n = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCNxA/CACNA1x family genes. [less ▲]

Detailed reference viewed: 152 (6 UL)
Full Text
Peer Reviewed
See detailMISCAST: MIssense variant to protein StruCture Analysis web SuiTe
Iqbal, Sumaiya; Hoksza, David UL; Pérez-Palma, Eduardo et al

in Nucleic Acids Research (2020)

Human genome sequencing efforts have greatly expanded, and a plethora of missense variants identified both in patients and in the general population is now publicly accessible. Interpretation of the ... [more ▼]

Human genome sequencing efforts have greatly expanded, and a plethora of missense variants identified both in patients and in the general population is now publicly accessible. Interpretation of the molecular-level effect of missense variants, however, remains challenging and requires a particular investigation of amino acid substitutions in the context of protein structure and function. Answers to questions like ‘Is a variant perturbing a site involved in key macromolecular interactions and/or cellular signaling?’, or ‘Is a variant changing an amino acid located at the protein core or part of a cluster of known pathogenic mutations in 3D?’ are crucial. Motivated by these needs, we developed MISCAST (missense variant to protein structure analysis web suite; http://miscast.broadinstitute.org/). MISCAST is an interactive and user-friendly web server to visualize and analyze missense variants in protein sequence and structure space. Additionally, a comprehensive set of protein structural and functional features have been aggregated in MISCAST from multiple databases, and displayed on structures alongside the variants to provide users with the biological context of the variant location in an integrated platform. We further made the annotated data and protein structures readily downloadable from MISCAST to foster advanced offline analysis of missense variants by a wide biological community. [less ▲]

Detailed reference viewed: 48 (1 UL)
Full Text
Peer Reviewed
See detailPrimary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine
Golebiewska, Anna UL; Hau, Ann-Christin; Oudin, Anais et al

E-print/Working paper (2020)

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term ... [more ▼]

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies. [less ▲]

Detailed reference viewed: 58 (1 UL)
Full Text
Peer Reviewed
See detailBi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
Chatron, Nicolas; Becker, Felicitas; Morsy, Herba et al

in Brain: a Journal of Neurology (2020)

Developmental and Epileptic Encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of ... [more ▼]

Developmental and Epileptic Encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathies caused by bi-allelic loss of function variants in GAD1, as presented by eleven patients from 6 independent consanguineous families. Seizure onset occurred in the two first months of life in all patients. All 10 patients from whom early disease history was available, presented seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early electroencephalography showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before four years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyzes the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele. [less ▲]

Detailed reference viewed: 29 (3 UL)
Full Text
Peer Reviewed
See detailMissing heritability in Parkinson’s disease: the emerging role of non‑coding genetic variation
Ohnmacht, Jochen UL; May, Patrick UL; Sinkkonen, Lasse UL et al

in Journal of Neural Transmission (2020)

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical ... [more ▼]

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease- and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future. [less ▲]

Detailed reference viewed: 48 (3 UL)
Full Text
Peer Reviewed
See detailGene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders
Lal, Dennis; May, Patrick UL; Perez-Palma, Eduardo et al

in Genome Medicine (2020), 12(28),

Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs ... [more ▼]

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 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 2,078 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 newly NDD -associated genes. [less ▲]

Detailed reference viewed: 74 (0 UL)
Full Text
Peer Reviewed
See detailExcess of singleton loss-of-function variants in Parkinson's disease contributes to genetic risk.
Bobbili, Dheeraj Reddy; Banda, Peter UL; Krüger, Rejko UL et al

in Journal of Medical Genetics (2020)

Background Parkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple ... [more ▼]

Background Parkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple variants associated with sporadic PD were discovered via association studies. Methods We studied the whole-exome sequencing data of 340 PD cases and 146 ethnically matched controls from the Parkinson’s Progression Markers Initiative (PPMI) and performed burden analysis for different rare variant classes. Disease prediction models were built based on clinical, non-clinical and genetic features, including both common and rare variants, and two machine learning methods. Results We observed a significant exome-wide burden of singleton loss-of-function variants (corrected p=0.037). Overall, no exome-wide burden of rare amino acid changing variants was detected. Finally, we built a disease prediction model combining singleton loss-of-function variants, a polygenic risk score based on common variants, and family history of PD as features and reached an area under the curve of 0.703 (95% CI 0.698 to 0.708). By incorporating a rare variant feature, our model increased the performance of the state-of-the-art classification model for the PPMI dataset, which reached an area under the curve of 0.639 based on common variants alone. Conclusion The main finding of this study is to highlight the contribution of singleton loss-of-function variants to the complex genetics of PD and that disease risk prediction models combining singleton and common variants can improve models built solely on common variants. [less ▲]

Detailed reference viewed: 63 (3 UL)
Full Text
Peer Reviewed
See detailIdentification of pathogenic variant enriched regions across genes and gene families
Perez-Palma, Eduardo; May, Patrick UL; Iqbal, Sumaiya et al

in Genome Research (2020), 30(1), 62-71

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 76,153 missense variants from patients. With this gene family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1,252 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,639 amino acids and 215 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I.=3.90-Inf, p-value = 2.72x10-11). Using the complete ClinVar variant set, we found that missense variants inside the identified regions are 106-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 106.15, 95% C.I = 70.66-Inf, p-value < 2.2 x 10-16). All pathogenic variant enriched regions (PERs) identified are available online through the “PER viewer” a user-friendly online platform for interactive data mining, visualization and download. In summary, our gene family burden analysis approach identified novel pathogenic variant enriched regions in protein sequences. This annotation can empower variant interpretation. [less ▲]

Detailed reference viewed: 205 (2 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 78 (7 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 85 (2 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 107 (6 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 277 (33 UL)
Full Text
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 ▲]

Detailed reference viewed: 209 (1 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 87 (2 UL)
Full Text
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 ▲]

Detailed reference viewed: 94 (0 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 99 (0 UL)
Full Text
Peer Reviewed
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 ▲]

Detailed reference viewed: 69 (4 UL)