title: Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.
abstract: Inherited and de novo genomic imbalances at chromosome 16p11.2 are associated with autism spectrum disorders (ASD), but the causative genes remain unknown. Among the genes located in this region, PRRT2 codes for a member of the synaptic SNARE complex that allows the release of synaptic vesicles. PRRT2 is a candidate gene for ASD since homozygote mutations are associated with intellectual disability and heterozygote mutations cause benign infantile seizures, paroxysmal dyskinesia, or hemiplegic migraine. Here, we explored the contribution of PRRT2 mutations in ASD by screening its coding part in a large sample of 1578 individuals including 431 individuals with ASD, 186 controls and 961 individuals from the human genome Diversity Panel. We detected 24 nonsynonymous variants, 1 frameshift (A217PfsX8) and 1 in-frame deletion of 6 bp (p.A361_P362del). The frameshift mutation was observed in a control with no history of neurological or psychiatric disorders. The p.A361_P362del was observed in two individuals with autism from sub-Saharan African origin. Overall, the frequency of PRRT2 deleterious variants was not different between individuals with ASD and controls. Remarkably, PRRT2 displays a highly significant excess of nonsynonymous (pN) vs synonymous (pS) mutations in Asia (pN/pS = 4.85) and Europe (pN/pS = 1.62) compared with Africa (pN/pS = 0.26; Asia vs Africa: P = 0.000087; Europe vs Africa P = 0.00035; Europe vs Asia P = P = 0.084). We also showed that whole genome amplification performed through rolling cycle amplification could artificially introduce the A217PfsX8 mutation indicating that this technology should not be performed prior to PRRT2 mutation screening. In summary, our results do not support a role for PRRT2 coding sequence variants in ASD, but provide an ascertainment of its genetic variability in worldwide populations that should help researchers and clinicians to better investigate the role of PRRT2 in human diseases.
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France; CNRS URA 2182 'Genes, synapses and cognition', Institut Pasteur, Paris, France; University Denis Diderot Paris 7, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huguet
authors.affiliation: INSERM, U975-CRICM, Institut du cerveau et de la moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France; CNRS 7225-CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Université Pierre et Marie Curie-Paris-6 (UPMC), UMR_S 975, Paris, France; Département de Génétique et de Cytogénétique, Unité fonctionnelle de génétique clinique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France; CNRS URA 2182 'Genes, synapses and cognition', Institut Pasteur, Paris, France; University Denis Diderot Paris 7, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lemière
authors.affiliation: Unit of Human Evolutionary Genetics, Institut Pasteur, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Patin
authors.affiliation: Unit of Human Evolutionary Genetics, Institut Pasteur, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laval
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France; CNRS URA 2182 'Genes, synapses and cognition', Institut Pasteur, Paris, France; University Denis Diderot Paris 7, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Ey
authors.affiliation: INSERM, U975-CRICM, Institut du cerveau et de la moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France; CNRS 7225-CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Université Pierre et Marie Curie-Paris-6 (UPMC), UMR_S 975, Paris, France; Département de Génétique et de Cytogénétique, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: INSERM, U955, Psychiatry Genetic team, Creteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.affiliation: INSERM, UMR_S901, Marseille, France; Aix-Marseille University, Marseille, France; Mediterranean Institute of Neurobiology (INMED), Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
authors.affiliation: Gillberg Neuropsychiatry Centre, University of Gothenburg, Göteborg, Sweden; Institute of Neuroscience and Physiology, Department of Pharmacology, Gothenburg University, Gothenburg, Sweden; Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.affiliation: INSERM, U975-CRICM, Institut du cerveau et de la moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France; CNRS 7225-CRICM, Hôpital Pitié-Salpêtrière, Paris, France; Université Pierre et Marie Curie-Paris-6 (UPMC), UMR_S 975, Paris, France; Département de Génétique et de Cytogénétique, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France; CNRS URA 2182 'Genes, synapses and cognition', Institut Pasteur, Paris, France; Fondation FondaMental, Créteil, France; Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France; CNRS URA 2182 'Genes, synapses and cognition', Institut Pasteur, Paris, France; University Denis Diderot Paris 7, Paris, France; Fondation FondaMental, Créteil, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
mesh_terms: D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human