SHANK1 Deletions in Males with Autism Spectrum Disorder

• Published in: American journal of human genetics Vol. 90; no. 5; pp. 879 - 887
• Main Authors: Sato, Daisuke, Lionel, Anath C., Leblond, Claire S., Prasad, Aparna, Pinto, Dalila, Walker, Susan, O'Connor, Irene, Russell, Carolyn, Drmic, Irene E., Hamdan, Fadi F., Michaud, Jacques L., Endris, Volker, Roeth, Ralph, Delorme, Richard, Huguet, Guillaume, Leboyer, Marion, Rastam, Maria, Gillberg, Christopher, Lathrop, Mark, Stavropoulos, Dimitri J., Anagnostou, Evdokia, Weksberg, Rosanna, Fombonne, Eric, Zwaigenbaum, Lonnie, Fernandez, Bridget A., Roberts, Wendy, Rappold, Gudrun A., Marshall, Christian R., Bourgeron, Thomas, Szatmari, Peter, Scherer, Stephen W.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 04.05.2012; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Adolescent; Adult; Autism; Basic Medicine; Biological and medical sciences; Canada; Child; Child clinical studies; Child Development Disorders; Child Development Disorders, Pervasive; Child Development Disorders, Pervasive - genetics; Child Development Disorders, Pervasive - physiopathology; Child, Preschool; Chromosomes; Cognitive science; Data processing; Developmental disorders; DNA Copy Number Variations; Europe; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Human health and pathology; Humans; Infantile autism; Intellectual Disability; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Life Sciences; Male; Medical and Health Sciences; Medical genetics; Medical Genetics and Genomics (including Gene Therapy); Medical sciences; Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Metabolism; Molecular and cellular biology; Mutation; Nerve Tissue Proteins; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Neurons - metabolism; Pedigree; Pervasive; Physiopathology; Preschool; Psychiatrics and mental health; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psykiatri; Sequence Deletion; Synapses; Synapses - genetics; Synapses - metabolism; Canada; Europe; Chromosomal aberration; Human; Autism; Pervasive developmental disorder; Deletion; Genetics; Male; Developmental disorder
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2012.03.017

Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers—but not female carriers—have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.