title: A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder.
abstract: BACKGROUND
  Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution.
  
  
  METHODS
  We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse.
  
  
  RESULTS
  The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development.
  
  
  CONCLUSIONS
  The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
authors: Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, Bologna 40126, Italy.
authors: Elena
authors: E
authors: Bacchelli
authors: Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, Bologna 40126, Italy.
authors: Fabiola
authors: F
authors: Ceroni
authors: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Dalila
authors: D
authors: Pinto
authors: Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, Bologna 40126, Italy.
authors: Silvia
authors: S
authors: Lomartire
authors: Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, Milan 20132, Italy.
authors: Maila
authors: M
authors: Giannandrea
authors: Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, Milan 20132, Italy ; Vita-Salute San Raffaele University, Milan 20132, Italy.
authors: Patrizia
authors: P
authors: D'Adamo
authors: Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.
authors: Elena
authors: E
authors: Bonora
authors: IRCCS Institute of Neurological Sciences, Bologna 40139, Italy ; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40139, Italy.
authors: Piero
authors: P
authors: Parchi
authors: Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone, Pisa 56128, Italy.
authors: Raffaella
authors: R
authors: Tancredi
authors: Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone, Pisa 56128, Italy.
authors: Agatino
authors: A
authors: Battaglia
authors: Department of Pharmacy and Biotechnology, University of Bologna, via Selmi 3, Bologna 40126, Italy.
authors: Elena
authors: E
authors: Maestrini
keywords: Alpha T-catenin; Autism spectrum disorder (ASD); CTNNA3; Cell adhesion; DNA copy number variants; αT-catenin