17 results on '"Delphine Bouteiller"'
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2. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.
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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
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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.
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- 2009
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3. SCN1A-related epilepsy with recessive inheritance: Two further families
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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
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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.
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- 2021
4. RAD51 Haploinsufficiency Causes Congenital Mirror Movements in Humans
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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)
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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.
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- 2012
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5. KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations
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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
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[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.
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- 2012
6. Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females
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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 )
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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.
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- 2011
7. Familial form of typical childhood absence epilepsy in a consanguineous context
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Amina Gargouri, Delphine Bouteiller, Hanen Abouda, Isabelle Gourfinkel-An, Christel Depienne, Riadh Gouider, Elisabeth Tournier-Lasserve, Florence Riant, Yosr Hizem, and Eric LeGuern
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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.
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- 2010
8. Autism, language delay and mental retardation in a patient with 7q11 duplication
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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)
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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.
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- 2007
9. Congenital mirror movements: Mutational analysis of RAD51 and DCC in 26 cases
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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
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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.
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- 2014
10. Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p
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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)
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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.
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- 2010
11. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome
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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]
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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.
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- 2010
12. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders
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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)
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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.
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- 2009
13. Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females
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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)
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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.
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- 2009
14. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia
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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
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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
15. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients
- Author
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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)
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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
16. Refinement of the 2p11.1-q12.2 locus responsible for cortical tremor associated with epilepsy and exclusion of candidate genes
- Author
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Stéphanie Baulac, Pierre Labauge, Eric LeGuern, Cyprian Popescu, Cécile Saint-Martin, Christel Depienne, Delphine Bouteiller, Céline Charon, Giovanni Stevanin, and Merle Ruberg
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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
17. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE
- Author
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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
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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
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