Author: "Delphine Bouteiller" - Searchworks@Jio Institute Digital Library Search Results

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1. Correction: Dabi et al. Clues for Improving the Pathophysiology Knowledge for Endometriosis Using Plasma Micro-RNA Expression. Diagnostics 2022, 12, 175

Author: Yohann Dabi, Stéphane Suisse, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Anne Puchar, Emile Daraï, and Sofiane Bendifallah
Subjects: n/a, Medicine (General), R5-920
Abstract: In the original publication [...]
Published: 2024
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2. C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

Author: Maria-Belen Lopez-Herdoiza, Stephanie Bauché, Baptiste Wilmet, Caroline Le Duigou, Delphine Roussel, Magali Frah, Jonas Béal, Gabin Devely, Susana Boluda, Petra Frick, Delphine Bouteiller, Sébastien Dussaud, Pierre Guillabert, Carine Dalle, Magali Dumont, Agnes Camuzat, Dario Saracino, Mathieu Barbier, Gaelle Bruneteau, Phillippe Ravassard, Manuela Neumann, Sophie Nicole, Isabelle Le Ber, Alexis Brice, and Morwena Latouche
Subjects: TDP-43, C9ORF72, FTD (frontotemporal dementia), ALS (amyotrophic lateral sclerosis), autophagy/lysosomal pathway, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS.
Published: 2023
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3. MicroRNome analysis generates a blood-based signature for endometriosis

Author: Sofiane Bendifallah, Yohann Dabi, Stéphane Suisse, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Anne Puchar, and Emile Daraï
Subjects: Medicine, Science
Abstract: Abstract Endometriosis, characterized by endometrial-like tissue outside the uterus, is thought to affect 2–10% of women of reproductive age: representing about 190 million women worldwide. Numerous studies have evaluated the diagnostic value of blood biomarkers but with disappointing results. Thus, the gold standard for diagnosing endometriosis remains laparoscopy. We performed a prospective trial, the ENDO-miRNA study, using both Artificial Intelligence (AI) and Machine Learning (ML), to analyze the current human miRNome to differentiate between patients with and without endometriosis, and to develop a blood-based microRNA (miRNA) diagnostic signature for endometriosis. Here, we present the first blood-based diagnostic signature obtained from a combination of two robust and disruptive technologies merging the intrinsic quality of miRNAs to condense the endometriosis phenotype (and its heterogeneity) with the modeling power of AI. The most accurate signature provides a sensitivity, specificity, and Area Under the Curve (AUC) of 96.8%, 100%, and 98.4%, respectively, and is sufficiently robust and reproducible to replace the gold standard of diagnostic surgery. Such a diagnostic approach for this debilitating disorder could impact recommendations from national and international learned societies.
Published: 2022
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4. Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Author: Christel Depienne, Sorana Ciura, Oriane Trouillard, Delphine Bouteiller, Elsa Leitã;o, Caroline Nava, Boris Keren, Yannick Marie, Justine Guegan, Sylvie Forlani, Alexis Brice, Mathieu Anheim, Yves Agid, Paul Krack, Philippe Damier, François Viallet, Jean-Luc Houeto, Franck Durif, Marie Vidailhet, Yulia Worbe, Emmanuel Roze, Edor Kabashi, and Andreas Hartmann
Subjects: tourette syndrome, gene, variant, susceptibility factor, opioid receptor, zebrafish, oprk1, Diseases of the musculoskeletal system, RC925-935, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.
Published: 2019
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5. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author: Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D. M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A. J. Tijssen, Arn M. J. M. van den Maagdenberg, and Christel Depienne
Subjects: Science
Abstract: Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
Published: 2019
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6. A Bioinformatics Approach to MicroRNA-Sequencing Analysis Based on Human Saliva Samples of Patients with Endometriosis

Author: Sofiane Bendifallah, Yohann Dabi, Stéphane Suisse, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Anne Puchar, and Emile Daraï
Subjects: endometriosis, miRNA, NGS, bioinformatics, saliva, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Endometriosis, defined by the presence of endometrium-like tissue outside the uterus, affects 2–10% of the female population, i.e., around 190 million women, worldwide. The aim of the prospective ENDO-miRNA study was to develop a bioinformatics approach for microRNA-sequencing analysis of 200 saliva samples for miRNAome expression and to test its diagnostic accuracy for endometriosis. Among the 200 patients, 76.5% (n = 153) had confirmed endometriosis and 23.5% (n = 47) had no endometriosis (controls). Small RNA-seq of 200 saliva samples yielded ~4642 M raw sequencing reads (from ~13.7 M to ~39.3 M reads/sample). The number of expressed miRNAs ranged from 1250 (outlier) to 2561 per sample. Some 2561 miRNAs were found to be differentially expressed in the saliva samples of patients with endometriosis compared with the control patients. Among these, 1.17% (n = 30) were up- or downregulated. Among these, the F1-score, sensitivity, specificity, and AUC ranged from 11–86.8%, 5.8–97.4%, 10.6–100%, and 39.3–69.2%, respectively. Here, we report a bioinformatic approach to saliva miRNA sequencing and analysis. We underline the advantages of using saliva over blood in terms of ease of collection, reproducibility, stability, safety, non-invasiveness. This report describes the whole saliva transcriptome to make miRNA quantification a validated, standardized, and reliable technique for routine use. The methodology could be applied to build a saliva signature of endometriosis.
Published: 2022
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7. Endometriosis Associated-miRNome Analysis of Blood Samples: A Prospective Study

Author: Sofiane Bendifallah, Yohann Dabi, Stéphane Suisse, Léa Delbos, Mathieu Poilblanc, Philippe Descamps, Francois Golfier, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Anne Puchar, and Emile Daraï
Subjects: endometriosis, miRNA, NGS, bioinformatics, Medicine (General), R5-920
Abstract: The aim of our study was to describe the bioinformatics approach to analyze miRNome with Next Generation Sequencing (NGS) of 200 plasma samples from patients with and without endometriosis. Patients were prospectively included in the ENDO-miRNA study that selected patients with pelvic pain suggestive of endometriosis. miRNA sequencing was performed using an Novaseq6000 sequencer (Illumina, San Diego, CA, USA). Small RNA-seq of 200 plasma samples yielded ~4228 M raw sequencing reads. A total of 2633 miRNAs were found differentially expressed. Among them, 8.6% (n = 229) were up- or downregulated. For these 229 miRNAs, the F1-score, sensitivity, specificity, and AUC ranged from 0–88.2%, 0–99.4%, 4.3–100%, and 41.5–68%, respectively. Utilizing the combined bioinformatic and NGS approach, a specific and broad panel of miRNAs was detected as being potentially suitable for building a blood signature of endometriosis.
Published: 2022
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8. Clues for Improving the Pathophysiology Knowledge for Endometriosis Using Plasma Micro-RNA Expression

Author: Yohann Dabi, Stéphane Suisse, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Anne Puchar, Emile Daraï, and Sofiane Bendifallah
Subjects: endometriosis, miRNA, pathophysiology, pathways, Medicine (General), R5-920
Abstract: The pathophysiology of endometriosis remains poorly understood. The aim of the present study was to investigate functions and pathways associated with the various miRNAs differentially expressed in patients with endometriosis. Plasma samples of the 200 patients from the prospective “ENDO-miRNA” study were analyzed and all known human miRNAs were sequenced. For each miRNA, sensitivity, specificity, and ROC AUC values were calculated for the diagnosis of endometriosis. miRNAs with an AUC ≥ 0.6 were selected for further analysis. A comprehensive review of recent articles from the PubMed, Clinical Trials.gov, Cochrane Library, and Web of Science databases was performed to identify functions and pathways associated with the selected miRNAs. In total, 2633 miRNAs were found in the patients with endometriosis. Among the 57 miRNAs with an AUC ≥ 0.6: 20 had never been reported before; one (miR-124-3p) had previously been observed in endometriosis; and the remaining 36 had been reported in benign and malignant disorders. miR-124-3p is involved in ectopic endometrial cell proliferation and invasion and plays a role in the following pathways: mTOR, STAT3, PI3K/Akt, NF-κB, ERK, PLGF-ROS, FGF2-FGFR, MAPK, GSK3B/β–catenin. Most of the remaining 36 miRNAs are involved in carcinogenesis through cell proliferation, apoptosis, and invasion. The three main pathways involved are Wnt/β–catenin, PI3K/Akt, and NF–KB. Our results provide evidence of the relation between the miRNA profiles of patients with endometriosis and various signaling pathways implicated in its pathophysiology.
Published: 2022
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9. Correction: Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in Resembles Dravet Syndrome but Mainly Affects Females.

Author: Christel Depienne, Delphine Bouteiller, Boris Keren, Emmanuel Cheuret, Karine Poirier, Oriane Trouillard, Baya Benyahia, Chloé Quelin, Wassila Carpentier, Sophie Julia, Alexandra Afenjar, Agnès Gautier, François Rivier, Sophie Meyer, Patrick Berquin, Marie Hélias, Isabelle Py, Serge Rivera, Nadia Bahi-Buisson, Isabelle Gourfinkel-An, Cécile Cazeneuve, Merle Ruberg, Alexis Brice, Rima Nabbout, and Eric LeGuern
Subjects: Genetics, QH426-470
Published: 2009
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10. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

Author: Christel Depienne, Delphine Bouteiller, Boris Keren, Emmanuel Cheuret, Karine Poirier, Oriane Trouillard, Baya Benyahia, Chloé Quelin, Wassila Carpentier, Sophie Julia, Alexandra Afenjar, Agnès Gautier, François Rivier, Sophie Meyer, Patrick Berquin, Marie Hélias, Isabelle Py, Serge Rivera, Nadia Bahi-Buisson, Isabelle Gourfinkel-An, Cécile Cazeneuve, Merle Ruberg, Alexis Brice, Rima Nabbout, and Eric Leguern
Subjects: Genetics, QH426-470
Abstract: Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.
Published: 2009
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11. Endometriosis-associated infertility diagnosis based on saliva microRNA signatures

Author: Yohann Dabi, Stéphane Suisse, Anne Puchar, Léa Delbos, Mathieu Poilblanc, Philippe Descamps, Julie Haury, Francois Golfier, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Emile Daraï, and Sofiane Bendifallah
Subjects: Reproductive Medicine, Obstetrics and Gynecology, Developmental Biology
Abstract: Can a saliva-based miRNA signature for endometriosis-associated infertility be designed and validated by analysing the human miRNome?The prospective ENDOmiARN study (NCT04728152) included 200 saliva samples obtained between January 2021 and June 2021 from women with pelvic pain suggestive of endometriosis. All patients underwent either laparoscopy, magnetic resonance imaging, or both. Patients diagnosed with endometriosis were allocated to one of two groups according to their fertility status. Data analysis consisted of identifying a set of miRNA biomarkers using next-generation sequencing, and development of a saliva-based miRNA signature of infertility among patients with endometriosis based on a random forest model.Among the 153 patients diagnosed with endometriosis, 24% (n = 36) were infertile and 76% (n = 117) were fertile. Small RNA-sequencing of the 153 saliva samples yielded approximately 3712 M raw sequencing reads (from ∼13.7 M to ∼39.3 M reads/sample). Of the 2561 known miRNAs, the feature selection method generated a signature of 34 miRNAs linked to endometriosis-associated infertility. After validation, the most accurate signature model had a sensitivity, specificity and area under the curve of 100%.A saliva-based miRNA signature for endometriosis-associated infertility is reported. Although the results still require external validation before using the signature in routine practice, this non-invasive tool is likely to have a major effect on care provided to women with endometriosis.
Published: 2023

12. Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation

Author: Nicolas Vallet, Sophie Le Grand, Louise Bondeelle, Bénédicte Hoareau, Aurélien Corneau, Delphine Bouteiller, Simon Tournier, Lucille Derivry, Armelle Bohineust, Marie Tourret, Delphine Gibert, Ethan Mayeur, Raphael Itzykson, Kim Pacchiardi, Brian Ingram, Stéphane Cassonnet, Patricia Lepage, Régis Peffault de Latour, Gérard Socié, Anne Bergeron, and David Michonneau
Subjects: Neoplasms, Immunology, Hematopoietic Stem Cell Transplantation, Humans, Cell Biology, Hematology, Azithromycin, Biochemistry, Metabolic Networks and Pathways, Stem Cell Transplantation
Abstract: Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients’ samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.
Published: 2022

13. SCN1A-related epilepsy with recessive inheritance: Two further families

Author: Julien Buratti, Isabelle Gourfinkel-An, Oriane Trouillard, Raffaella Moretti, Cyril Mignot, Delphine Bouteiller, Vincent des Portes, Patricia Moreau, Christel Depienne, Boris Keren, Agnès Rastetter, Lionel Arnaud, Joseph Toulouse, Caroline Nava, and Eric LeGuern
Subjects: Medizin, Epilepsies, Myoclonic, Biology, Asymptomatic, Seizures, Febrile, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Dravet syndrome, 030225 pediatrics, medicine, Humans, Missense mutation, Allele, Gene, Genetics, Seizure threshold, General Medicine, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Phenotype, Mutation, Pediatrics, Perinatology and Child Health, Epilepsy syndromes, Neurology (clinical), medicine.symptom, Epileptic Syndromes, 030217 neurology & neurosurgery
Abstract: Background Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. Methods and results We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. Conclusion This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.
Published: 2021

14. Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity

Author: Melissa Saichi, Christophe Rousseau, Elise Amblard, Lucile Massenet-Regad, Sarantis Korniotis, Floriane Noël, Vassili Soumelis, Jasna Medvedovic, Zakaria Ait Hamou, Delphine Bouteiller, Y. Marie, Maha Zohra Ladjemi, and Frédéric Pène
Subjects: Antigen presentation, Major histocompatibility complex, Antiviral Agents, Monocytes, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Antigen, Interferon, MHC class I, CIITA, Humans, Medicine, Antigen-presenting cell, Antigens, Viral, 030304 developmental biology, Antigen Presentation, 0303 health sciences, biology, Effector, Sequence Analysis, RNA, business.industry, COVID-19, TLR9, TLR7, Dendritic Cells, Cell Biology, Dendritic cell, Cell biology, 030220 oncology & carcinogenesis, Immunology, biology.protein, Single-Cell Analysis, business, Viral load, medicine.drug
Abstract: COVID-19 can lead to life-threatening acute respiratory failure, characterized by simultaneous increase in inflammatory mediators and viral load. The underlying cellular and molecular mechanisms remain unclear. We performed single-cell RNA-sequencing to establish an exhaustive high-resolution map of blood antigen-presenting cells (APC) in 7 COVID-19 patients with moderate or severe pneumonia, at day-1 and day-4 post-admission, and two healthy donors. We generated a unique dataset of 31,513 high quality APC, including monocytes and rare dendritic cell (DC) subsets. We uncovered multiprocess and previously unrecognized defects in anti-viral immune defense in specific APC compartments from severe patients: i) increase of pro-apoptotic genes exclusively in pDC, which are key effectors of antiviral immunity, ii) sharp decrease of innate sensing receptors, TLR7 and DHX9, in pDC and cDC1, respectively, iii) down-regulation of antiviral effector molecules, including Interferon stimulated genes (ISG) in all monocyte subsets, and iv) decrease of MHC class II-related genes, and MHC class II transactivator (CIITA) activity in cDC2, suggesting a viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore defective immune defense.
Published: 2021

15. Salivary MicroRNA Signature for Diagnosis of Endometriosis

Author: Sofiane Bendifallah, Stéphane Suisse, Anne Puchar, Léa Delbos, Mathieu Poilblanc, Philippe Descamps, Francois Golfier, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Yohann Dabi, Emile Daraï, Centre Expert en Endométriose [CHU Tenon] (GRC6 C3E), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ziwig Health, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hospices Civils de Lyon (HCL), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Gestionnaire, HAL Sorbonne Université 5
Subjects: endometriosis, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, saliva, diagnostic, signature, miRNA, Medicine, General Medicine, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics
Abstract: International audience; Background: Endometriosis diagnosis constitutes a considerable economic burden for the healthcare system with diagnostic tools often inconclusive with insufficient accuracy. We sought to analyze the human miRNAome to define a saliva-based diagnostic miRNA signature for endometriosis. Methods: We performed a prospective ENDO-miRNA study involving 200 saliva samples obtained from 200 women with chronic pelvic pain suggestive of endometriosis collected between January and June 2021. The study consisted of two parts: (i) identification of a biomarker based on genome-wide miRNA expression profiling by small RNA sequencing using next-generation sequencing (NGS) and (ii) development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a Random Forest algorithm. Results: Among the 200 patients, 76.5% (n = 153) were diagnosed with endometriosis and 23.5% (n = 47) without (controls). Small RNA-seq of 200 saliva samples yielded ~4642 M raw sequencing reads (from ~13.7 M to ~39.3 M reads/sample). Quantification of the filtered reads and identification of known miRNAs yielded ~190 M sequences that were mapped to 2561 known miRNAs. Of the 2561 known miRNAs, the feature selection with Random Forest algorithm generated after internally cross validation a saliva signature of endometriosis composed of 109 miRNAs. The respective sensitivity, specificity, and AUC for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%. Conclusions: The ENDO-miRNA study is the first prospective study to report a saliva-based diagnostic miRNA signature for endometriosis. This could contribute to improving early diagnosis by means of a non-invasive tool easily available in any healthcare system.
Published: 2021

16. Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Author: Zakaria Ait-Hamou, Floriane Noel, Maha Zohra Ladjemi, Sarantis Korniotis, Yannick Marie, Frédéric Pène, Delphine Bouteiller, Christophe Rousseau, Jasna Medvedovic, Elise Amblard, Vassili Soumelis, Lucile Massenet, and Melissa Saichi
Subjects: biology, Effector, Interferon, Antigen presentation, MHC class I, Immunology, biology.protein, CIITA, medicine, Dendritic cell, TLR7, Antigen-presenting cell, medicine.drug
Abstract: COVID-19 can lead to life-threatening acute respiratory failure, characterized by simultaneous increase in inflammatory mediators and viral load. The underlying cellular and molecular mechanisms remain unclear. We performed single-cell RNA-sequencing to establish an exhaustive high-resolution map of blood antigen-presenting cells (APC) in 7 COVID-19 patients with moderate or severe pneumonia, at day-1 and day-4 post-admission, and two healthy donors. We generated a unique dataset of 31,513 high quality APC, including monocytes and rare dendritic cell (DC) subsets. We uncovered multiprocess and previously unrecognized defects in anti-viral immune defense in specific APC compartments from severe patients: i) increase of pro-apoptotic genes exclusively in pDC, which are key effectors of antiviral immunity, ii) sharp decrease of innate sensing receptors, TLR7 and DHX9, in pDC and cDC1, respectively, iii) down-regulation of antiviral effector molecules, including Interferon stimulated genes (ISG) in all monocyte subsets, and iv) decrease of MHC class II-related genes, and MHC class II transactivator (CIITA) activity in cDC2, suggesting a viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore defective immune defense.
Published: 2020

17. Juvenile myoclonic epilepsy phenotype in a family with Unverricht-Lundborg disease

Author: Amina Gargouri, Berrechid, Mouna, Bendjebara, Delphine, Bouteiller, Amina, Nasri, Jean-Noël, Peuvion, Yannick, Marie, Stéphanie, Baulac, Saloua, Mrabet, Théo, Ribierre, Cecile, Cazeneuve, Imenkacem, Eric, Leguern, and Riadh, Gouider
Subjects: Adult, Male, Phenotype, Adolescent, Unverricht-Lundborg Syndrome, Mutation, Myoclonic Epilepsy, Juvenile, Humans, Female, Genetic Testing, Myoclonic Epilepsies, Progressive
Abstract: Unverricht-Lundborg disease (ULD), an autosomal recessive progressive myoclonus epilepsy, is due to an expansion, or less commonly a mutation, of the cystatin B (CSTB) gene. We report a clinical and molecular study of a Tunisian ULD family with five affected members presenting with a juvenile myoclonic epilepsy (JME)-like phenotype. The expansion of dodecamers was detected by a deamination/PCR assay. The expression profiles of CSTB and other candidate modifying genes, cathepsin B and cystatin C, were established by quantitative RT-PCR, and their respective transcription levels were compared with those from patients with a classic picture of ULD. Three patients had a fixed phenotype mimicking JME after 29 years of evolution. Only a discrete dysarthria was noticed in the two other patients. No correlation was observed between transcription level and severity of disease. Genetic screening should be performed in patients with a JME-like phenotype, when careful examination reveals discrete atypical signs of JME. This particular phenotype may be due to modifying genes and/or gene-environment interactions which require further clarification.
Published: 2019

18. PRRT2 mutations: A major cause of paroxysmal kinesigenic dyskinesia in the European population

Author: Domitille Gras, Emmanuel Roze, Thierry Billette de Villemeur, Charles Pierre Jedynak, Fabienne Picard, Christine Tranchant, Mathieu Anheim, Cécile Gaudebout, Dominique Steschenko, Pierre Burbaud, Delphine Bouteiller, David Devos, Alexandra Durr, Isabelle Lagroua, Marie Vidailhet, Alexis Brice, David Grabli, Christel Depienne, Diane Doummar, Cyril Mignot, and Aurélie Méneret
Subjects: Adult, Pediatrics, medicine.medical_specialty, Movement disorders, Mutation/genetics, Choreoathetosis, Nerve Tissue Proteins, Genetic analysis, White People, Epilepsy, Epilepsy, Benign Neonatal/diagnosis/genetics, Seizures/diagnosis/genetics, Chorea, Seizures, medicine, Nerve Tissue Proteins/genetics, Humans, European Continental Ancestry Group/genetics, Membrane Proteins/genetics, Age of Onset, Dyskinesias, business.industry, Membrane Proteins, Syndrome, European population, Paroxysmal dyskinesia, musculoskeletal system, medicine.disease, Epilepsy, Benign Neonatal, ddc:616.8, Pedigree, Mutation, Chorea/diagnosis/genetics, Dyskinesias/diagnosis/genetics, cardiovascular system, Neurology (clinical), Age of onset, medicine.symptom, business, PRRT2
Abstract: Objective: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by recurrent attacks of hyperkinetic movements. PKD can be isolated or associated with benign infantile seizures as part of the infantile convulsions with choreoathetosis (ICCA) syndrome. Mutations in the PRRT2 gene were recently identified in patients with PKD and ICCA. We studied the prevalence of PRRT2 mutations and characteristics of the patients in a European population of patients with PKD and ICCA. Methods: Patients were recruited through the 1996−2011 database of our DNA bank, to which physicians refer DNA with a putative diagnosis and clinical information. Two movement disorders experts reviewed the information on patients with a putative diagnosis of PKD. Patients who fulfilled the criteria for PKD and ICCA were included. The PRRT2 coding sequence was analyzed by direct sequencing. Results: Among 42 index cases of unrelated families referred with a putative diagnosis of PKD, a total of 34 patients, including 32 with isolated PKD and 2 with ICCA, were selected for genetic analysis. Mutations introducing premature termination codons were identified in 22 of 34 patients including 13 of 14 families and 9 of 20 patients with sporadic cases. The previously described c.649dupC/pArg217ProfsX8 and c.629dupC/pAla211SerfsX14 were present, respectively, in 17 patients and 1 patient; we also report 3 novel mutations: c.649delC/pArg217GlufsX12 in 2 patients, and c.562C>T/pGln188X and c.649C>T/pArg217X, each in 1 patient. The group with mutations was characterized by a younger age at onset (9 years) compared with the patients without mutations (15 years; p Conclusion: Mutations in PRRT2 are a major cause of PKD in familial and sporadic cases in the European population.
Published: 2012

19. RAD51 Haploinsufficiency Causes Congenital Mirror Movements in Humans

Author: Delphine Bouteiller, Vanessa Brochard, Emmanuel Roze, Christel Depienne, Jean-Paul Saraiva, Sabine Meunier, Kailash P. Bhatia, Aurélie Méneret, Ségolène Billot, Constance Flamand-Roze, Rosine Wehrlé, Stephan Klebe, Jean-Christophe Corvol, Isabelle Dusart, Massimo Cincotta, Sergiu Groppa, Y. Marie, Norbert Brueggemann, Giovanni Stevanin, Wassila Carpentier, Marion Gaussen, Marie Vidailhet, Alexis Brice, Christine Klein, Fanny Charbonnier-Beaupel, Développement et plasticité des réseaux neuronaux = Development and Plasticity of Neural Networks (NPS-14), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Heterozygote, DNA Repair, DNA repair, RAD51, Down-Regulation, Receptors, Cell Surface, Haploinsufficiency, Biology, medicine.disease_cause, Congenital Abnormalities, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Report, Netrin, medicine, Genetics, Humans, DNA Breaks, Double-Stranded, Exome, Genetics(clinical), Nerve Growth Factors, RNA, Messenger, Homologous Recombination, Genetics (clinical), Exome sequencing, 030304 developmental biology, Family Health, 0303 health sciences, Mutation, Dyskinesias, Movement Disorders, Tumor Suppressor Proteins, Motor Cortex, Netrin-1, DCC Receptor, Axons, Pedigree, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rad51 Recombinase, 030217 neurology & neurosurgery, Genome-Wide Association Study, Motor cortex
Abstract: International audience; Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.
Published: 2012
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20. KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

Author: Emeline Mundwiller, Bat-El Zimmerman, Israela Lerer, Hamid Azzedine, Gabor Gyapay, Stephan Klebe, Vincent Meyer, Wassila Carpentier, Alexander Lossos, Agnès Rastetter, Elodie Martin, Laurent Orlando, Alexis Brice, Moriya Gamliel, Cecilia Marelli, Alexandra Durr, Magdalena Nawara, Ruth Sheffer, Marion Gaussen, Delphine Bouteiller, Khalid H. El-Hachimi, Giovanni Stevanin, Adel Misk, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hadassah Hebrew University Medical Center [Jerusalem], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: [SDV]Life Sciences [q-bio], Mutation, Missense, Kinesins, Genes, Recessive, Biology, medicine.disease_cause, Article, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Hereditary sensory and autonomic neuropathy, Genetics, medicine, Humans, Missense mutation, Family, Genetics (clinical), 030304 developmental biology, KIF1A, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Spastic Paraplegia, Hereditary, Genetic heterogeneity, Homozygote, Chromosome Mapping, medicine.disease, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Chromosomes, Human, Pair 2, Chromosomal region, Candidate Gene Analysis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: International audience; The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.
Published: 2012

21. Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females

Author: Eric LeGuern, François Rivier, Brigitte Gilbert-Dussardier, Denys Chaigne, Delphine Bouteiller, Karine Poirier, Agathe Roubertie, Anne Dusser, Sandra Whalen, Marie Bru, Dominique Steschenko, Oriane Trouillard, Isabelle Gourfinkel-An, Stéphanie Baulac, Alexis Arzimanoglou, Agnès Gautier, Dorota Hoffman-Zacharska, Christel Depienne, Anna Kaminska, Hélène Maurey, Cyril Mignot, Gaetan Lesca, Annie Lannuzel, Marilyn Lackmy-Port-Lis, Rima Nabbout, Patrick Berquin, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Pôle d'Epileptologie, AP-HP, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neuropédiatrie, CHU Hôpital Nord Amiens, Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Clinique Sainte-Odile, Strasbourg, Unité de Neurologie Pédiatrique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Serice de Neuropédiatrie, Institute of Mother and Child Department of Medical Genetics, Department of neurology, CHU Pointe-à-Pitre/Abymes [Guadeloupe], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de neurologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hôpital Mère-Enfant, CHU de Nantes, Service de Genetique medicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Hôpital, CHU Trousseau [APHP], Pavillon E, Laboratoire de Genetique, Unité d'Epileptologie Pédiatrique, Service de Neurologie Pédiatrique et des Maladies Métaboliques, AP-HP, Hôpital Robert Debré, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, and Centre hospitalier universitaire de Poitiers ( CHU Poitiers )
Subjects: Adult, Male, PCDH19, Adolescent, Febrile seizures, Protocadherin, Mutation in Brief, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, Epilepsy, Young Adult, 0302 clinical medicine, Genetics, medicine, Humans, Family history, Child, Genetics (clinical), X chromosome, cognitive function, 030304 developmental biology, 0303 health sciences, Mutation, Polymorphism, Genetic, Point mutation, Life Sciences, Infant, Exons, Middle Aged, medicine.disease, Cadherins, Protocadherins, Pedigree, Child, Preschool, Female, microdeletion, Generalized epilepsy with febrile seizures plus, 030217 neurology & neurosurgery, Gene Deletion
Abstract: International audience; Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation.
Published: 2011

22. Familial form of typical childhood absence epilepsy in a consanguineous context

Author: Amina Gargouri, Delphine Bouteiller, Hanen Abouda, Isabelle Gourfinkel-An, Christel Depienne, Riadh Gouider, Elisabeth Tournier-Lasserve, Florence Riant, Yosr Hizem, and Eric LeGuern
Subjects: Genetics, Familial form, CACNG2, biology, Direct sequencing, business.industry, Context (language use), CACNB4, medicine.disease, Epilepsy, Childhood absence epilepsy, Neurology, medicine, biology.protein, Neurology (clinical), business, Gene, Neuroscience
Abstract: Summary Causative genes for childhood absence epilepsy (CAE) are unknown partly because families are small or phenotypically heterogeneous. In five consanguineous Tunisian families with at least two sibs with CAE, 14 patients fulfilled the diagnostic criteria for CAE (Epilepsia 1989;30:389–399). Linkage analyses or direct sequencing excluded CACNG2, CACNA1A, CACNB4, and CACNA2D2, orthologs of genes responsible for autosomal recessive (AR) absence seizures in mice. These families will help identify (a) gene(s) responsible for CAE.
Published: 2010

23. Autism, language delay and mental retardation in a patient with 7q11 duplication

Author: Christel Depienne, Oriane Trouillard, Delphine Bouteiller, Eric LeGuern, Marion Leboyer, Baya Benyahia, Alain Verloes, Alexis Brice, Delphine Héron, Catalina Betancur, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research was supported by Fondation de France, Fondation pour la Recherche Médicale, Fondation France Télécom, INSERM and Assistance Publique-Hôpitaux de Paris., Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Pediatrics, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Language delay, autism, Neurological disorder, Biology, mental retardation, Article, 03 medical and health sciences, 0302 clinical medicine, Gene duplication, Intellectual disability, Genetics, medicine, Mild dysmorphism, language delay, Genetics (clinical), 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, business.industry, 030305 genetics & heredity, General Medicine, Interstitial duplication, Nucleic acid amplification technique, Microdeletion syndrome, medicine.disease, 7q11, Developmental disorder, duplication, Male patient, Microsatellite Analysis, Autism, business, Letter to JMG, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams-Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date: one with severe language delay and the three others with variable developmental, psychomotor and language delay. OBJECTIVE AND METHODS: In this study, we screened 206 patients with autism spectrum disorders for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. RESULTS: We identified one male patient with a de novo interstitial duplication of the entire WBCR of paternal origin. The patient had autistic disorder, severe language delay and mental retardation, with very mild dysmorphic features. CONCLUSION: We report the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism, and extends the phenotype initially reported. These findings also support the existence of one or several genes in 7q11.23 sensitive to gene dosage and involved in the development of language and social interaction.
Published: 2007

24. Hypomorphic variants of cationic amino acid transporter 3 in males with autism spectrum disorders

Author: Caroline, Nava, Johanna, Rupp, Jean-Paul, Boissel, Cyril, Mignot, Agnès, Rastetter, Claire, Amiet, Aurélia, Jacquette, Céline, Dupuits, Delphine, Bouteiller, Boris, Keren, Merle, Ruberg, Anne, Faudet, Diane, Doummar, Anne, Philippe, Didier, Périsse, Claudine, Laurent, Nicolas, Lebrun, Vincent, Guillemot, Jamel, Chelly, David, Cohen, Delphine, Héron, Alexis, Brice, Ellen I, Closs, Christel, Depienne, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Department of pharmacology, Johannes Gutemberg Universität Mainz, Service de neuropédiatrie [Trousseau], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de psychiatrie enfant et adolescent, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre diagnostic autisme, CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), iCONICS, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Institut des Systèmes Intelligents et de Robotique ( ISIR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), CHU Trousseau [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut des Systèmes Intelligents et de Robotique (ISIR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de psychiatrie enfant et adolescent [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université
Subjects: Male, Exome sequencing, Chromosome X, Autism Spectrum Disorder, Molecular Sequence Data, Clinical Biochemistry, Molecular Conformation, Mutation, Missense, Loss of Heterozygosity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Xenopus laevis, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Gene Frequency, Animals, Humans, Biotinylation, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Chromosomes, Human, X, Epilepsy, Cell Membrane, Organic Chemistry, Brain, Autism spectrum disorders, Pedigree, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Oocytes, Oligogenism, Amino Acid Transport Systems, Basic, Original Article, Cationic amino acid transporter
Abstract: Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors. Electronic supplementary material The online version of this article (doi:10.1007/s00726-015-2057-3) contains supplementary material, which is available to authorized users.
Published: 2015

25. Congenital mirror movements: Mutational analysis of RAD51 and DCC in 26 cases

Author: Jean Louis Golmard, Marcello Romano, Karolina Dzieżyc, Delphine Bouteiller, Pierre Bitoun, Christel Depienne, Luc Defebvre, Oriane Trouillard, Florence Riant, Simona Fiori, M. Cincotta, Simone Rossi, Pierre Pollak, Stephan Klebe, Linda De Meirleir, Marie Vidailhet, Ghislaine Plessis, Chloé Quélin, Aurélie Méneret, Alberto J. Espay, Ana Westenberger, Sabine Rudnik-Schöneborn, Isabelle Lagroua, Alexis Brice, Susan Sklower Brooks, Russell C. Dale, Diane Doummar, Julia Wickert, Emmanuel Roze, Alessandra Borgheresi, Clinical sciences, Reproduction and Genetics, and Neurogenetics
Subjects: Population, Nonsense mutation, DNA Mutational Analysis, Mutation, Missense, Receptors, Cell Surface, Biology, medicine.disease_cause, Severity of Illness Index, Article, Frameshift mutation, symbols.namesake, Arts and Humanities (miscellaneous), Receptors, medicine, Missense mutation, Humans, education, Codon, Exome, Genetics, Sanger sequencing, education.field_of_study, Mutation, Movement Disorders, Tumor Suppressor Proteins, fungi, DCC Receptor, Pedigree, Carrier Proteins, Codon, Nonsense, Neurology (clinical), Nonsense, Cell Surface, symbols, Missense
Abstract: Objective: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51 . Methods: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. Results: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC , one DCC mutation leading to a frameshift, 5 missense variants in DCC , and 2 missense variants in RAD51 . All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls ( p RAD51 and DCC ). Conclusion: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.
Published: 2014

26. A novel DCC mutation and genetic heterogeneity in congenital mirror movements

Author: Vanessa Brochard, Fabio Giovannelli, Christel Depienne, Sabine Meunier, Cécile Hubsch, M. Cincotta, Sergiu Groppa, M. Vidailhet, Alexis Brice, Jean-Christophe Corvol, Delphine Bouteiller, Emmanuel Roze, Ségolène Billot, Stephan Klebe, and C. Flamand
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Neurology, Deleted in Colorectal Cancer, Pain, Stereotypic Movement Disorder, Locus (genetics), Severity of Illness Index, Upper Extremity, Genetic Heterogeneity, Severity of illness, Netrin, medicine, Humans, Age of Onset, Aged, Dyskinesias, Genetic heterogeneity, fungi, Middle Aged, medicine.disease, Pedigree, Stereotypic movement disorder, Genes, DCC, Phenotype, Mutation, Female, Neurology (clinical), France, Age of onset, Psychology
Abstract: Objective: DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the body's midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. Methods: We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. Results: The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. Conclusion: DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity. Neurology (R) 2011; 76:260-264
Published: 2011

27. Familial form of typical childhood absence epilepsy in a consanguineous context

Author: Hanen, Abouda, Yosr, Hizem, Amina, Gargouri, Christel, Depienne, Delphine, Bouteiller, Florence, Riant, Elisabeth, Tournier-Lasserve, Isabelle, Gourfinkel-An, Eric, LeGuern, and Riadh, Gouider
Subjects: Male, Tunisia, Adolescent, Genetic Linkage, Black People, Electroencephalography, Pedigree, Consanguinity, Phenotype, Epilepsy, Absence, Humans, Anticonvulsants, Family, Female, Calcium Channels, Child
Abstract: Causative genes for childhood absence epilepsy (CAE) are unknown partly because families are small or phenotypically heterogeneous. In five consanguineous Tunisian families with at least two sibs with CAE, 14 patients fulfilled the diagnostic criteria for CAE (Epilepsia 1989; 30:389-399). Linkage analyses or direct sequencing excluded CACNG2, CACNA1A, CACNB4, and CACNA2D2, orthologs of genes responsible for autosomal recessive (AR) absence seizures in mice. These families will help identify (a) gene(s) responsible for CAE.
Published: 2010

28. Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p

Author: Pierre Labauge, Christel Depienne, Lucien Rumbach, Edouard Hirsch, Delphine Bouteiller, Cécile Saint-Martin, Marie Vidailhet, G. Stevanin, Eloi Magnin, Eric LeGuern, Emmanuelle Apartis, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Les chimiokines et leurs récepteurs : fonctions cérébrales et neuroendocriniennes, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Adult, Male, Benign adult familial myoclonic epilepsy, Genetic Linkage, Epilepsies, Myoclonic, Locus (genetics), Neurological disorder, Central nervous system disease, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Tremor, medicine, Humans, Polymorphic Microsatellite Marker, Genetic Testing, Genotyping, Aged, 030304 developmental biology, Cerebral Cortex, Genetics, 0303 health sciences, Gene map, business.industry, Chromosome Mapping, Middle Aged, medicine.disease, Genetic Loci, Chromosomes, Human, Pair 5, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. METHODS: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. RESULTS: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. CONCLUSIONS: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.
Published: 2010

29. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome

Author: Charlotte Dravet, Oriane Trouillard, Claude Adam, Cécile Saint-Martin, Clothilde Rivier-Ringenbach, Sophie Dupont, Eric LeGuern, Stéphanie Baulac, Isabelle Gourfinkel-An, Marie-Anne Barthez-Carpentier, Marie-Odile Livet, Rima Nabbout, Delphine Bouteiller, Delphine Héron, Denis Graber, Nathalie Villeneuve, Christel Depienne, Agnès Gautier, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique de l'Enfant, CH La Rochelle, Service de Neuropédiatrie [Clocheville], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Gatien de Clocheville, Serice de Neuropédiatrie, Service de Neurologie, Hôpital Henri Gastaut, Service de Pédiatrie, Centre Hospitalier du Pays d'Aix, Service de pédiatre-Néonatologie, CH Villefranche s/Saone, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de référence des épilepsies rares, CHRU Tours-Hôpital Gatien de Clocheville, Epilepsies de l'Enfant et Plasticité Cérébrale ( U1129 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Peer, Hal, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Proband, Male, medicine.medical_specialty, DNA Mutational Analysis, Mutation, Missense, Epilepsies, Myoclonic, Nerve Tissue Proteins, Genetic screening/counselling, Biology, medicine.disease_cause, Sodium Channels, 03 medical and health sciences, 0302 clinical medicine, Dravet syndrome, Molecular genetics, Genetics, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Missense mutation, Humans, Genetic Predisposition to Disease, Clinical genetics, Allele, Child, Genetics (clinical), 030304 developmental biology, Sequence Deletion, Family Health, 0303 health sciences, Mutation, Syndrome, medicine.disease, Phenotype, 3. Good health, Pedigree, Epilepsy and seizures, NAV1.1 Voltage-Gated Sodium Channel, Codon, Nonsense, Medical genetics, Female, RNA Splice Sites, 030217 neurology & neurosurgery
Abstract: International audience; Background. Mutations in SCN1A can cause Genetic Epilepsy with Febrile Seizures Plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. Objectives and patients. We studied 19 selected families with at least one DS patients to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele-specific assays. Results. Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04% to 85%. In the 6 remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. Conclusion. Our results indicate that mosaicism is found in at least 7% of families with at least one DS patient and that it accounts for 68 % (13/19) of inherited mutations associated with DS. On the contrary, in the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.
Published: 2010

30. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders

Author: Daniel Moreno-De-Luca, Gudrun Nygren, Eric LeGuern, Pauline Chaste, Marion Leboyer, Delphine Bouteiller, Catalina Betancur, Baya Benyahia, Svenny Kopp, Christel Depienne, Aurélie Gennetier, Alain Verloes, Alexis Brice, Lydie Burglen, Maria Råstam, Jean-Pierre Siffroi, Sandra Chantot-Bastaraud, Maria E. Johansson, Delphine Héron, Richard Delorme, Oriane Trouillard, Christopher Gillberg, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute of Child Health [London], University College of London [London] (UCL), This research was supported by Fondation de France, INSERM, Fondation pour la Recherche Médicale, Fondation France Télécom, Cure Autism Now, Assistance Publique-Hôpitaux de Paris, and the Swedish Science Council., Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Betancur, Catalina, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Gene Dosage, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Gene Dosage, 0302 clinical medicine, MESH: DNA Methylation, MESH: Child, deletion, Child, Genetics, 0303 health sciences, chromosome 15, Uniparental disomy, 3. Good health, MLPA, duplication, Child, Preschool, Female, Prader-Willi Syndrome, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, MESH: Autistic Disorder, autism, Biology, Dup15q, MESH: Angelman Syndrome, 03 medical and health sciences, Chromosome 15, Angelman syndrome, MESH: Uniparental Disomy, Happy puppet syndrome, mental disorders, medicine, Humans, MESH: Chromosome Aberrations, Multiplex ligation-dependent probe amplification, Autistic Disorder, Biological Psychiatry, 030304 developmental biology, Chromosome Aberrations, MESH: Adolescent, Chromosomes, Human, Pair 15, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Child, Preschool, MESH: Adult, DNA Methylation, Uniparental Disomy, medicine.disease, MESH: Male, Developmental disorder, MESH: Gene Deletion, MESH: Prader-Willi Syndrome, MESH: Microsatellite Repeats, Genomic imprinting, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion, Microsatellite Repeats, MESH: Chromosomes, Human, Pair 15
Abstract: International audience; BACKGROUND: Maternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD. METHODS: A total of 522 patients belonging to 430 families were screened for deletions, duplications, and methylation abnormalities involving 15q11-q13 with multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified four patients with 15q11-q13 abnormalities: a supernumerary chromosome 15, a paternal interstitial duplication, and two subjects with Angelman syndrome, one with a maternal deletion and the other with a paternal uniparental disomy. CONCLUSIONS: Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening.
Published: 2009

31. Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family

Author: Marie Vidailhet, Cécile Saint-Martin, Eloi Magnin, Pierre Labauge, Lucien Rumbach, Delphine Bouteiller, Christel Depienne, Eric LeGuern, and Emmanuelle Apartis
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Genetic Linkage, Epilepsies, Myoclonic, Electroencephalography, Asymptomatic, Central nervous system disease, Epilepsy, Young Adult, Genetic linkage, Evoked Potentials, Somatosensory, Reflex, Tremor, Medicine, Humans, Photosensitivity Disorders, Young adult, Gait Disorders, Neurologic, Aged, medicine.diagnostic_test, business.industry, Chromosome Mapping, Middle Aged, medicine.disease, Surgery, Pedigree, Neurology, Migraine, Female, Neurology (clinical), France, medicine.symptom, Lod Score, business, Myoclonus
Abstract: Introduction Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2. Methods The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2). Results Mean age at onset in the 17 living patients was 28.8 years (range 24–41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40 years) and eight were of unknown status (asymptomatic aged lesser than 40 years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded. Conclusion This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.
Published: 2009

32. Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Author: Baya Benyahia, Marie Hélias, François Rivier, Chloé Quélin, Patrick Berquin, Nadia Bahi-Buisson, Merle Ruberg, Sophie Julia, Cécile Cazeneuve, Sophie Meyer, Christel Depienne, Wassila Carpentier, Isabelle Gourfinkel-An, Alexis Brice, Karine Poirier, Oriane Trouillard, Delphine Bouteiller, Isabelle Py, Boris Keren, Alexandra Afenjar, Rima Nabbout, Serge Rivera, Emmanuel Cheuret, Agnès Gautier, Eric LeGuern, Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Toulouse [Toulouse], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Gestionnaire, Hal Sorbonne Université, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Proband, Male, Cancer Research, Chromosomes, Human, Pair 22, Epilepsies, Myoclonic, medicine.disease_cause, Epilepsy, 0302 clinical medicine, Missense mutation, Child, Genetics (clinical), Genetics and Genomics/Genetics of Disease, Genetics, Genetics and Genomics/Medical Genetics, 0303 health sciences, Mutation, Sex Characteristics, Cadherins, Pedigree, Child, Preschool, Genetics and Genomics/Gene Discovery, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, lcsh:QH426-470, Adolescent, Cell Biology/Neuronal Signaling Mechanisms, Nonsense mutation, Molecular Sequence Data, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Dravet syndrome, Neurological Disorders/Epilepsy, medicine, SNP, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Base Sequence, Point mutation, medicine.disease, Protocadherins, lcsh:Genetics, Cell Biology/Cell Adhesion, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism., Author Summary Severe epilepsies associated with cognitive impairment in children are multifarious and most affected patients are sporadic cases. Thus, there is a challenge to identify which of these epilepsies are genetically determined, since their sporadic status excludes the use of classical genetic approaches. We have used microarrays, which are new technological tools to investigate the whole genome of an individual, to search for small genomic abnormalities and identify novel genes in 41 patients with a clinically well-characterized severe infantile epileptic disorder called Dravet syndrome. We have identified PCDH19, a new gene on chromosome X, which was recently found in a familial epileptic syndrome known as female-limited epilepsy and cognitive impairment. This gene was mutated in 12 out of 74 patients with clinical features compatible with Dravet syndrome. Eleven of these patients were females. The single male with a PCDH19 deficiency was mosaic in his skin; i.e., some of his cells express PCDH19 and others do not. This finding suggests that a new pathogenic mechanism—cellular interference—is associated with an unusual X-linked mode of inheritance in which females are more frequently affected than males.
Published: 2009

33. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Author: Stéphane Thobois, Alexandra Durr, Agnès Camuzat, Diane Doummar, Cécile Cazeneuve, Emmanuel Roze, Chankannira Sân, Alexis Brice, Delphine Bouteiller, Brigitte Chabrol, Myriem Abada, Pierre Castelnau, David Grabli, Fabienne Clot, Estelle Fedirko, Karine Nguyen, G. Ponsot, Alana Ward, Michael Hutchinson, Marie Vidailhet, Roger Gil, Pierre Landrieu, Fabienne Picard, Annick Toutain, Philippe Damier, and Eric LeGuern
Subjects: Adult, Male, medicine.medical_specialty, Heterozygote, Tyrosine 3-Monooxygenase, Adolescent, Dopamine, Ubiquitin-Protein Ligases, Dopamine Agents, Dystonic Disorders/drug therapy/*genetics/metabolism, Biology, medicine.disease_cause, Parkin, Levodopa, Alcohol Oxidoreductases/genetics, Young Adult, Internal medicine, medicine, Tyrosine 3-Monooxygenase/genetics, Humans, Point Mutation, Ubiquitin-Protein Ligases/genetics, Age of Onset, Sepiapterin reductase, GTP Cyclohydrolase, Child, Genetics, Dystonia, Mutation, Parkinsonism, Point mutation, Biopterin/*analogs & derivatives/biosynthesis, Middle Aged, medicine.disease, Biopterin, nervous system diseases, ddc:616.8, Levodopa/*therapeutic use, Alcohol Oxidoreductases, Endocrinology, Sepiapterin reductase deficiency, Dystonic Disorders, Child, Preschool, Female, Neurology (clinical), Dopamine/*biosynthesis, GTP Cyclohydrolase/genetics, Dystonic disorder, Dopamine Agents/*therapeutic use
Abstract: Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.
Published: 2009

34. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients

Author: Cécile Cazeneuve, Cécile Saint-Martin, Stéphanie Baulac, Alexis Arzimanoglou, Isabelle Gourfinkel-An, Christel Depienne, Oriane Trouillard, B Abert, Wassila Carpentier, Rima Nabbout, Delphine Bouteiller, Boris Keren, Agnès Gautier, Eric LeGuern, Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Nantes (CHU Nantes), Hospices Civils de Lyon (HCL), Épilepsie de l'enfant et plasticité cérébrale (Inserm U663), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, Mutation rate, [SDV]Life Sciences [q-bio], Epilepsies, Myoclonic, Nerve Tissue Proteins, Biology, medicine.disease_cause, Sodium Channels, 03 medical and health sciences, 0302 clinical medicine, Dravet syndrome, Genetics, medicine, Humans, Missense mutation, Multiplex ligation-dependent probe amplification, Genetics (clinical), 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Point mutation, Infant, Newborn, Infant, Sequence Analysis, DNA, Gene rearrangement, medicine.disease, 3. Good health, NAV1.1 Voltage-Gated Sodium Channel, [SDV] Life Sciences [q-bio], Female, Haploinsufficiency, Nucleic Acid Amplification Techniques, Gene Deletion, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; INTRODUCTION:Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI).OBJECTIVE:To characterise in more detail the mutation spectrum associated with Dravet syndrome.METHODS:A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened.RESULTS:SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients.CONCLUSION:These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.
Published: 2008

35. Refinement of the 2p11.1-q12.2 locus responsible for cortical tremor associated with epilepsy and exclusion of candidate genes

Author: Stéphanie Baulac, Pierre Labauge, Eric LeGuern, Cyprian Popescu, Cécile Saint-Martin, Christel Depienne, Delphine Bouteiller, Céline Charon, Giovanni Stevanin, and Merle Ruberg
Subjects: Male, Candidate gene, Essential Tremor, MEDLINE, Locus (genetics), Epilepsies, Myoclonic, Biology, Cellular and Molecular Neuroscience, Epilepsy, Genetics, medicine, Humans, Gene, Genetics (clinical), Lod score, Genes, Dominant, Chromosome Mapping, medicine.disease, Molecular medicine, Human genetics, Pedigree, Chromosomes, Human, Pair 2, Female, Lod Score
Published: 2007

36. The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V

Author: Merle Ruberg, A. Barois, Vincent Meininger, Delphine Bouteiller, Alexis Brice, Jean Pouget, Hamid Azzedine, R. Ben Yaou, Odile Dubourg, and Eric LeGuern
Subjects: Glycine-tRNA Ligase, Pathology, medicine.medical_specialty, Heterozygote, DNA Mutational Analysis, Motor nerve, Biology, medicine.disease_cause, Asymptomatic, Risk Assessment, Glycine—tRNA ligase, Muscular Atrophy, Spinal, Risk Factors, medicine, Missense mutation, Humans, Family, Genetic Predisposition to Disease, Age of Onset, Mutation, Incidence, Anatomy, Penetrance, medicine.anatomical_structure, Jews, Female, Neurology (clinical), France, Age of onset, medicine.symptom, Sensory nerve
Abstract: Background: Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (dSMA) is a heterogeneous group of disorders characterized almost exclusively by degeneration of motor nerve fibers, predominantly in the distal part of the limbs. One subtype, dHMN type V (dHMN-V), is transmitted by autosomal dominant inheritance and predominantly involves the hands. It is allelic with Charcot–Marie–Tooth disease 2D (CMT2D), in which a similar phenotype is associated with sensory signs. Missense mutations in the glycyl-tRNA synthetase ( GARS ) gene have been recently reported in families with either dHMN-V, CMT2D, or both. Methods: The authors searched for GARS mutations in eight dHMN-V families. Results: The authors found the G526R missense mutation in three families (16 patients) of Algerian Sephardic Jewish origin. All patients shared a common disease haplotype, suggestive of a founder effect. The clinical phenotype consists of a slowly progressive, purely motor distal neuropathy. It starts in the hands in most patients, but also in both distal upper and lower limbs or in distal lower limbs alone. The age at onset in symptomatic individuals was between the second to fourth decades, but four mutation carriers were still asymptomatic, two of whom were already age 49 years. Electrophysiology showed that the motor fibers of the median nerve were the most affected in upper limbs. Sensory nerve action potentials were normal. Conclusions: The age at onset of patients with the G526R mutation in the GARS gene varied widely, but the clinical and electrophysiologic presentation was uniform and progressed slowly. Glycyl-tRNA synthetase mutations are a frequent cause of familial distal hereditary motor neuropathy type V but, because of the reduced penetrance of the disease, could also account for isolated cases.
Published: 2006

37. Tremblement cortical familial associé à une épilepsie : localisation génétique en 5p

Author: Lucien Rumbach, Marie Vidailhet, Delphine Bouteiller, Christel Depienne, Giovanni Stevanin, Cécile Saint-Martin, Pierre Labauge, Eloi Magnin, Eric LeGuern, and Emmanuelle Apartis
Subjects: Neurology, business.industry, Medicine, Neurology (clinical), business
Published: 2010

38. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE

Author: Didier Périsse, Clement A. Gautier, Guillaume Huguet, Anne Faudet, Claudine Laurent, C Dupuits, Christopher Gillberg, Delphine Bouteiller, Cyril Mignot, Delphine Héron, Sandra Whalen, David Cohen, Mylène Gilleron, Marion Leboyer, Boris Keren, Thomas Bourgeron, Marion Gérard, Alexis Brice, C. Depienne, Alexandra Afenjar, Agnès Rastetter, Foudil Lamari, Richard Delorme, Aurélia Jacquette, Caroline Nava, S Caillet, and Bruno Leheup
Subjects: Adult, Male, Candidate gene, TMLHE, Nonsense mutation, Biology, medicine.disease_cause, Polymerase Chain Reaction, Mixed Function Oxygenases, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genes, X-Linked, medicine, Humans, Missense mutation, Exome, Family, Sex Distribution, Child, Genetic Association Studies, Biological Psychiatry, X chromosome, 030304 developmental biology, Genetics, Chromosomes, Human, X, 0303 health sciences, Mutation, carnitine, Autism spectrum disorders, medicine.disease, Psychiatry and Mental health, Child Development Disorders, Pervasive, male excess, Case-Control Studies, chromosome X, Autism, Original Article, next-generation sequencing, Female, 030217 neurology & neurosurgery
Abstract: The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.
Published: 2012

39. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author: Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
Published: 2019

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