title: Maternally inherited genetic variants of CADPS2 are present in autism spectrum disorders and intellectual disability patients.
abstract: Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Graziano
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Minopoli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bacchelli
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Magini
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Diquigiovanni
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lomartire
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianco
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Vargiolu
authors.affiliation: Department of Neurology, University of Bologna, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.affiliation: CRBA, S. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Marasco
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy CRBA, S. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Vilma
authors.initials: V
authors.lastname: Mantovani
authors.affiliation: Molecular Genetics of Renal Disorders Unit, Division of Genetics and Cell Biology San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
authors.affiliation: Molecular Genetics of Renal Disorders Unit, Division of Genetics and Cell Biology San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Trudu
authors.affiliation: Department of Neurology, University of Bologna, Bologna, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Parmeggiani
authors.affiliation: Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.affiliation: Unit of Child Neuropsychiatry, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mazzone
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maestrini
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy marco.seri@unibo.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D060066:Protein Interaction Maps; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017384:Sequence Deletion; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C479428:CADPS2 protein, human; C480975:CAPS2 protein, mouse; D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D033921:Vesicular Transport Proteins
keywords: CADPS2; autism spectrum disorders; intellectual disability; monoallelic expression; mutation screening
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