Contribution of SHANK3 Mutations to Autism Spectrum Disorder

• Published in: American journal of human genetics Vol. 81; no. 6; pp. 1289 - 1297
• Main Authors: Moessner, Rainald, Marshall, Christian R., Sutcliffe, James S., Skaug, Jennifer, Pinto, Dalila, Vincent, John, Zwaigenbaum, Lonnie, Fernandez, Bridget, Roberts, Wendy, Szatmari, Peter, Scherer, Stephen W.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.12.2007; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Autism; Autistic Disorder; Biological and medical sciences; Biological variation; Carrier Proteins - genetics; Child clinical studies; Chromosome Mapping; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 22; Developmental disorders; Diagnostic tests; DNA - chemistry; DNA - genetics; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Humans; Infantile autism; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Nerve Tissue Proteins; Pedigree; Protein folding; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Sequence Deletion; Translocation, Genetic; Canada; Human; Autism; Nervous system diseases; Genetics; Developmental disorder; Mutation; Neurological disorder; Spectrum
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1086/522590

Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.