title: Copy number and sequence variants implicate APBA2 as an autism candidate gene.
abstract: We recently reported an autistic proband and affected sibling with maternally inherited microduplications within the 15q13.1 and 15q13.3 regions that contain a total of 4 genes. The amyloid precursor protein-binding protein A2 (APBA2) gene is located within the 15q13.1 duplication and encodes a neuronal adaptor protein essential to synaptic transmission that interacts directly with NRXN1 at the presynaptic membrane. We interpreted this as evidence for a putative role of APBA2 in autism as larger maternal duplications of 15q11-q13 are the most common known cause of autism. We therefore resequenced 512 subjects with autism spectrum disorder (ASD) and 463 controls, and identified 7 novel nonsynonymous coding variants in ASD subjects compared with 4 in controls. Five of the seven variants in the ASD group were predicted to affect protein function, alter residues conserved across 18 species, or both. All of the variants for which parental DNA was available were inherited. We also found two different nonsynonymous variants in two siblings with autism: (1) a paternally inherited heterozygous 6 bp deletion and (2) a maternally inherited heterozygous missense mutation, the latter also found in a single control. These results indicate compound heterozygous mutations of APBA2 in this autism sibship. The co-occurrence of two nonsynonymous mutations in both affected siblings in a single family, each transmitted from a different unaffected parent, suggest a role for APBA2 mutations in rare individuals with ASD.
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois 60637-5415, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Babatz
authors.forename: Ravinesh A
authors.initials: RA
authors.lastname: Kumar
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Sudi
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Susan L
authors.initials: SL
authors.lastname: Christian
mesh_terms: D000483:Alleles; D015820:Cadherins / Q000235:genetics*; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D004843:Epistasis, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: C491636:APBA2 protein, human; D015820:Cadherins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules