title: Systematic genotype-phenotype analysis of autism susceptibility loci implicates additional symptoms to co-occur with autism.
abstract: Many genetic studies in autism have been performed, resulting in the identification of multiple linkage regions and cytogenetic aberrations, but little unequivocal evidence for the involvement of specific genes exists. By identifying novel symptoms in these patients, enhanced phenotyping of autistic individuals not only improves understanding and diagnosis but also helps to define biologically more homogeneous groups of patients, improving the potential to detect causative genes. Supported by recent copy number variation findings in autism, we hypothesized that for some susceptibility loci, autism resembles a contiguous gene syndrome, caused by aberrations within multiple (contiguous) genes, which jointly increases autism susceptibility. This would result in various different clinical manifestations that might be rather atypical, but that also co-occur with autism. To test this hypothesis, 13 susceptibility loci, identified through genetic linkage and cytogenetic analyses, were systematically analyzed. The Online Mendelian Inheritance in Man database was used to identify syndromes caused by mutations in the genes residing in each of these loci. Subsequent analysis of the symptoms expressed within these disorders allowed us to identify 33 symptoms (significantly more than expected, P=0.037) that were over-represented in previous reports mapping to these loci. Some of these symptoms, including seizures and craniofacial abnormalities, support our hypothesis as they are already known to co-occur with autism. These symptoms, together with ones that have not previously been described to co-occur with autism, might be considered for use as inclusion or exclusion criteria toward defining etiologically more homogeneous groups for molecular genetic studies of autism.
authors: Rudolf Magnus Institute of Neurosciences, Department of Psychiatry, University Medical Centre, Heidelberglaan, Utrecht, The Netherlands.
authors: Jacobine E
authors: JE
authors: Buizer-Voskamp
authors: Lude
authors: L
authors: Franke
authors: Wouter G
authors: WG
authors: Staal
authors: Emma
authors: E
authors: van Daalen
authors: Chantal
authors: C
authors: Kemner
authors: Roel A
authors: RA
authors: Ophoff
authors: Jacob As
authors: JA
authors: Vorstman
authors: Herman
authors: H
authors: van Engeland
authors: Cisca
authors: C
authors: Wijmenga
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D016000:Cluster Analysis; D057225:Data Mining; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans