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1. Impact of a frequent nearsplice SOD1 variant in Amyotrophic Lateral Sclerosis: optimizing SOD1 genetic screening for gene therapy opportunities

Author

Stéphanie Millecamps, Aude-Marie Grapperon, Serge Lumbroso, François Salachas, Patrick Vourc'h, Aude Chiot, Delphine Bohl, Cécile Cazeneuve, Emilien Bernard, Anne-Laure Fauret-Amsellem, Kevin Mouzat, William Camu, Maria del Mar Amador, Christian S Lobsiger, Philippe Corcia, Beata Gyorgy, Séverine Boillée, Jean-Christophe Antoine, Shahram Attarian, Elisa Teyssou, Annie Verschueren, Yannick Marie, Claire Guissart, Jean-Philippe Camdessanché, Danielle Seilhean, Eric Leguern, François Muratet, Vincent Meininger, Justine Guegan, 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 Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centres de référence pour la sclérose latérale amyotrophique [CHU Pitié-Salpêtrière], 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), Hôpital privé des Peupliers (Paris), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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 Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Gestionnaire, HAL Sorbonne Université 5, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU Saint-Etienne], and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)

Subjects
MESH: Mutation, MESH: Pedigree, Genetic enhancement, animal diseases, [SDV]Life Sciences [q-bio], SOD1, Disease, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, MESH: Phenotype, 03 medical and health sciences, 0302 clinical medicine, MESH: Aged, 80 and over, medicine, Missense mutation, MESH: Superroxide Dismutase-1, Amyotrophic lateral sclerosis, Gene, MESH: Amyotrophic Lateral Sclerosis, 030304 developmental biology, Genetics, MESH: Aged, MESH: Genetic Therapy, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Middle Aged, MESH: Genetic Testing, nutritional and metabolic diseases, MESH: Adult, medicine.disease, Phenotype, MESH: Male, 3. Good health, nervous system diseases, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, nervous system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Surgery, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery
Abstract

ObjectiveMutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic.MethodsWe analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.ResultsWe identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.ConclusionsOur results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.

Published
2021
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2. New advances in Amyotrophic Lateral Sclerosis genetics: towards gene therapy opportunities for familial and young cases

Author

Stéphanie Millecamps, Elisa Teyssou, Maria-Del-Mar Amador, François Muratet, Séverine Boillée, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centres de référence pour la sclérose latérale amyotrophique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Gestionnaire, HAL Sorbonne Université 5, 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 Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Motor neuron diseases, Genetic counseling, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, pathogenic mutation, TARDBP, frontotemporal dementia, 03 medical and health sciences, 0302 clinical medicine, inclusion body myopathy, C9orf72, Medicine, Humans, 030212 general & internal medicine, Genetic Testing, Amyotrophic lateral sclerosis, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Amyotrophic Lateral Sclerosis, Oligogenic Inheritance, Genetic Therapy, medicine.disease, Penetrance, 3. Good health, [SDV] Life Sciences [q-bio], Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Neurology (clinical), Paget's disease of bone, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

International audience; Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.

Published
2021
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3. Genetic screening of ANXA11 revealed novel mutations linked to Amyotrophic Lateral Sclerosis

Author

Selma Machat, Elisa Teyssou, Vincent Meininger, Yannick Marie, Géraldine Lautrette, Beata Gyorgy, Stéphanie Millecamps, Philippe Couratier, Séverine Boillée, Mélanie Ferrien, Danielle Seilhean, Cécile Cazeneuve, François Muratet, Thierry Larmonier, Justine Guegan, François Salachas, Pascal Cintas, Safaa Saker, Nadine Le Forestier, Maria-Del-Mar Amador, William Camu, Eric LeGuern, 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), Centres de référence pour la sclérose latérale amyotrophique [CHU Pitié-Salpêtrière], 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 référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), CHU Limoges, Généthon, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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 Sclérose Latérale amyotrophique [CHU Toulouse], Département Neurologie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital privé des Peupliers (Paris), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neuropathologie [CHU Pitié Salpêtrière], Gestionnaire, HAL Sorbonne Université 5, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Sclérose Latérale Amyotrophique et maladies, Unité de neurophysiologie clinique [CHU Toulouse], and CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, Male, Aging, Pathology, medicine.medical_specialty, Annexins, Datasets as Topic, ANXA11, frontotemporal dementia, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, medicine, Humans, Exome, Motor neuron disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive decline, Amyotrophic lateral sclerosis, Genetic Association Studies, neuropathology, business.industry, General Neuroscience, Neurodegeneration, Amyotrophic Lateral Sclerosis, FTD, Frontotemporal lobar degeneration, Motor neuron, Spinal cord, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Mutation, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, Frontotemporal Lobar Degeneration, ALS, Annexin A11, business, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene.

Published
2021
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4. Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS

Author

Jean-Philippe Camdessanché, Emilien Bernard, Jean-Christophe Antoine, Guillaume Banneau, Etienne Allart, Maria-Del-Mar Amador, François Muratet, Elisa Teyssou, Gabrielle Rudolf, Giovanni Stevanin, Christine Tranchant, Véronique Danel-Brunaud, Marie-Céline Fleury, Stéphanie Millecamps, Mathieu Anheim, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie et Pathologie du Mouvement, Hôpital Roger Salengro, Centre Hospitalier Universitaire (CHU) de Lille, CHU de Lille, Service de neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), 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), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service de Neurologie [Hospices civils de Lyon - Hôpital Pierre Wertheimer], Hospices Civils de Lyon (HCL)-Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), MILLECAMPS, Stéphanie, 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 Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Hereditary spastic paraplegia, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, 0302 clinical medicine, C9orf72, medicine, Spasticity, Amyotrophic lateral sclerosis, Exome, Tetraplegia, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Bulbar palsy, Genetics, 0303 health sciences, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology (clinical), medicine.symptom, business, Trinucleotide repeat expansion, 030217 neurology & neurosurgery
Abstract

ObjectiveThe aim of this study was to evaluate whether mutations in ERLIN2, known to cause SPG18, a recessive hereditary spastic paraplegia (SP) responsible for the degeneration of the upper motor neurons leading to weakness and spasticity restricted to the lower limbs, could contribute to amyotrophic lateral sclerosis (ALS), a distinct and more severe motor neuron disease (MND), in which the lower motor neurons also profusely degenerates, leading to tetraplegia, bulbar palsy, respiratory insufficiency, and ultimately the death of the patients.MethodsWhole-exome sequencing was performed in a large cohort of 200 familial ALS and 60 sporadic ALS after a systematic screening for C9orf72 hexanucleotide repeat expansion. ERLIN2 variants identified by exome analysis were validated using Sanger analysis. Segregation of the identified variant with the disease was checked for all family members with available DNA.ResultsHere, we report the identification of ERLIN2 mutations in patients with a primarily SP evolving to rapid progressive ALS, leading to the death of the patients. These mutations segregated with the disease in a dominant (V168M) or recessive (D300V) manner in these families or were found in apparently sporadic cases (N125S).ConclusionsInheritance of ERLIN2 mutations appears to be, within the MND spectrum, more complex that previously reported. These results expand the clinical phenotype of ERLIN2 mutations to a severe outcome of MND and should be considered before delivering a genetic counseling to ERLIN2-linked families.

Published
2019
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5. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations

Author

Maria del Pilar Trelles, François Muratet, Alexander Kolevzon, Yitzchak Frank, Reymundo Lozano, Allison Durkin, J. Lloyd Holder, Catalina Betancur, Paige M. Siper, Silvia De Rubeis, Danielle Halpern, A. Ting Wang, Jordana Weissman, Joseph D. Buxbaum, Betancur, Catalina, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Psychiatry, Department of Neurology, Department of Pediatircs, Department of Genetics and Genomic Sciences, Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medecine-Texas Children's Hospital [Houston, USA], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Molecular Neuropsychiatry, Department of Neuroscience, Friedman Brain Institute, The Mindich Child Health and Development Institute, This work was supported by grants from the Beatrice and Samuel A. SeaverFoundation, the Phelan-McDermid Syndrome Foundation, NIMH (R34MH100276-01 to AK and R21 MH107839 to JDB), and NINDS (U54 NS092090-01 to AK and K08 NS091381 to JLH). SDR is a Seaver fellow. JLH is funded bythe Robbins Foundation. CB is a Research Director at INSERM., Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences 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), and 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)

Subjects
Male, 0301 basic medicine, Chromosomes, Human, Pair 22, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Intellectual disability, Chromosome Disorders, Haploinsufficiency, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, Neurodevelopmental disorder, Autism spectrum disorder, Child, SHANK3, Genetics, Phenotype, Hypotonia, 3. Good health, Psychiatry and Mental health, 22q13 deletion syndrome, Child, Preschool, Female, Allelic heterogeneity, Chromosome Deletion, medicine.symptom, Adult, Adolescent, Nerve Tissue Proteins, Sequence variants, 03 medical and health sciences, Developmental Neuroscience, medicine, Humans, Point Mutation, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, Point mutation, medicine.disease, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Phelan-McDermid syndrome, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Background Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. Electronic supplementary material The online version of this article (10.1186/s13229-018-0205-9) contains supplementary material, which is available to authorized users.

Published
2018
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6. Prospective investigation of FOXP1 syndrome

Author

Paige M. Siper, Heather C Mefford, Maria del Pilar Trelles, Silvia De Rubeis, Arianne S. Wallace, Jennifer S. Beighley, Joseph D. Buxbaum, Reymundo Lozano, Alexander Kolevzon, Morgan Kelly, Yitzchak Frank, Allison Durkin, Jennifer Gerdts, Raphael Bernier, François Muratet, Daniele Di Marino, and Evan E. Eichler

Subjects
0301 basic medicine, Male, Autism Spectrum Disorder, Developmental Disabilities, Bioinformatics, medicine.disease_cause, lcsh:RC346-429, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Prospective Studies, Child, Mutation, Forkhead Transcription Factors, 3. Good health, Psychiatry and Mental health, Phenotype, Autism spectrum disorder, Child, Preschool, Medical genetics, Female, Protein Binding, medicine.medical_specialty, Adolescent, Mutation, Missense, Frameshift mutation, 03 medical and health sciences, Developmental Neuroscience, Intellectual Disability, medicine, Humans, Amino Acid Sequence, Genetic Testing, Psychiatry, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Language Disorders, Polymorphism, Genetic, business.industry, Research, DNA, medicine.disease, Protein Structure, Tertiary, Repressor Proteins, 030104 developmental biology, Autism, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Background Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. Methods Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5–17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. Results We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. Conclusions This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome. Electronic supplementary material The online version of this article (10.1186/s13229-017-0172-6) contains supplementary material, which is available to authorized users.

Published
2017

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