Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

• Published in: Journal of medical genetics Vol. 48; no. 1; pp. 48 - 54
• Main Authors: Pagnamenta, Alistair T, Khan, Hameed, Walker, Susan, Gerrelli, Dianne, Wing, Kirsty, Bonaglia, Maria Clara, Giorda, Roberto, Berney, Tom, Mani, Elisa, Molteni, Massimo, Pinto, Dalila, Le Couteur, Ann, Hallmayer, Joachim, Sutcliffe, James S, Szatmari, Peter, Paterson, Andrew D, Scherer, Stephen W, Vieland, Veronica J, Monaco, Anthony P
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.01.2011; BMJ Publishing Group; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adolescent; Autism; autistic; Autistic Disorder - genetics; Base Sequence; Behavior; Biological and medical sciences; Cadherins - genetics; Cadherins - metabolism; CDH8; Child; Child clinical studies; Chromosome Deletion; Chromosomes, Human, Pair 16 - genetics; Classical genetics, quantitative genetics, hybrids; CNV; Communication; Developmental disorders; Disability; DNA Copy Number Variations - genetics; DNA Mutational Analysis; Epilepsy; Family; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene loci; General aspects. Genetic counseling; Genetic Linkage; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human - genetics; Genomes; Human; Humans; in situ; Infantile autism; Intelligence Tests; Internet; Learning disabilities; Learning Disabilities - genetics; Male; Medical genetics; Medical sciences; Mental disorders; Molecular and cellular biology; molecular genetics; Molecular Sequence Data; neurology; Original; Pedigree; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; synapse; Young Adult; United States > US; California; Genetic mapping; Human; Microdeletion; Nervous system diseases; Family study; Pathogenesis; Cell adhesion molecule; Developmental disorder; Cadherin; Genetic determinism; Autism; Learning disability; Genetic linkage; Predisposition; Genetics; Peak; Neurological disorder; Molecular genetics; Neurology
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2010.079426

BackgroundAutism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD.MethodsIn this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos.ResultsThe deletion of chr16: 60 025 584–61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527–60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex.ConclusionRare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD.