Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypical, ... Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypical, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options. - Genetic Heterogeneity of Autism Autism is considered to be a complex multifactorial disorder involving many genes. Accordingly, several loci have been identified, some or all of which may contribute to the phenotype. Included in this entry is AUTS1, which has been mapped to chromosome 7q22. Other susceptibility loci include AUTS3 (608049), which maps to chromosome 13q14; AUTS4 (608636), which maps to chromosome 15q11; AUTS5 (606053), which maps to chromosome 2q; AUTS6 (609378), which maps to chromosome 17q11; AUTS7 (610676), which maps to chromosome 17q21; AUTS8 (607373), which maps to chromosome 3q25-q27; AUTS9 (611015), which maps to chromosome 7q31; AUTS10 (611016), which maps to chromosome 7q36; AUTS11 (610836), which maps to chromosome 1q41; AUTS12 (610838), which maps to chromosome 21p13-q11; AUTS13 (610908), which maps to chromosome 12q14; AUTS14A (611913), which has been found in patients with a deletion of a region of 16p11.2; AUTS14B (614671), which has been found in patients with a duplication of a region of 16p11.2; AUTS15 (612100), associated with mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36; AUTS16 (613410), associated with mutation in the SLC9A9 gene (608396) on chromosome 3q24; AUTS17 (613436), associated with mutation in the SHANK2 gene (603290) on chromosome 11q13; and AUTS18 (615032), associated with mutation in the CHD8 gene (610528). (NOTE: the symbol 'AUTS2' has been used to refer to a gene on chromosome 7q11 (KIAA0442; 607270) and therefore is not used as a part of this autism locus series.) There are several X-linked forms of autism susceptibility: AUTSX1 (300425), associated with mutations in the NLGN3 gene (300336); AUTSX2 (300495), associated with mutations in NLGN4 (300427); AUTSX3 (300496), associated with mutations in MECP2 (300005); AUTSX4 (300830), associated with variation in the region on chromosome Xp22.11 containing the PTCHD1 gene (300828); AUTSX5 (300847), associated with mutations in the RPL10 gene (312173); and AUTSX6 (300872), associated with an exon 2 deletion in the TMLHE gene (300777). Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
The DSM-IV (American Psychiatric Association, 1994) specifies several diagnostic criteria for autism. In general, patients with autism exhibit qualitative impairment in social interaction, as manifest by impairment in the use of nonverbal behaviors such as eye-to-eye gaze, facial ... The DSM-IV (American Psychiatric Association, 1994) specifies several diagnostic criteria for autism. In general, patients with autism exhibit qualitative impairment in social interaction, as manifest by impairment in the use of nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures, failure to develop appropriate peer relationships, and lack of social sharing or reciprocity. Patients have impairments in communication, such as a delay in, or total lack of, the development of spoken language. In patients who do develop adequate speech, there remains a marked impairment in the ability to initiate or sustain a conversation, as well as stereotyped or idiosyncratic use of language. Patients also exhibit restricted, repetitive and stereotyped patterns of behavior, interests, and activities, including abnormal preoccupation with certain activities and inflexible adherence to routines or rituals. In his pioneer description of infantile autism, Kanner (1943) defined the disorder as 'an innate inability to form the usual, biologically provided affective contact with people.' Kanner (1943) noted that in most cases the child's behavior was abnormal from early infancy, and he suggested the presence of an inborn, presumably genetic, defect. In a review, Smalley (1997) stated that mental retardation is said to be present in approximately 75% of cases of autism, seizures in 15 to 30% of cases, and electroencephalographic abnormalities in 20 to 50% of cases. In addition, approximately 15 to 37% of cases of autism have a comorbid medical condition, including 5 to 14% with a known genetic disorder or chromosomal anomaly. The 4 most common associations include fragile X syndrome (300624), tuberous sclerosis (see 191100), 15q duplications (AUTS4; 608636), and untreated phenylketonuria (PKU; 261600). Significant associations at a phenotypic level may reflect disruptions in a common neurobiologic pathway, common susceptibility genes, or genes in linkage disequilibrium. The autism spectrum disorder shows a striking sex bias, with a male:female ratio of idiopathic autism estimated at 4-10:1, and with an increase in this ratio as the intelligence of the affected individuals increases (Folstein and Rosen-Sheidley, 2001). Lainhart et al. (2002) stated that approximately 20% of children with autism appear to have relatively normal development during the first 12 to 24 months of life. This period of relative normalcy gradually or suddenly ends and is followed by a period of regression, characterized most prominently by a significant loss of language skills, after which the full autism syndrome becomes evident. Rarely, children with autism may exhibit hyperlexia, or precocious reading (238350). Among a group of 66 children with pervasive developmental disorder, Burd et al. (1985) identified 4 with hyperlexia. Cohen et al. (2005) discussed several genetic disorders consistently associated with autism, including fragile X syndrome, tuberous sclerosis, Angelman syndrome (105830), Down syndrome (190685), Sanfilippo syndrome (252900), Rett syndrome (312750) and other MECP2-related disorders, phenylketonuria, Smith-Magenis syndrome (SMS; 182290), 22q13 deletion syndrome (606232), Cohen syndrome (COH1; 216550), adenylosuccinate lyase deficiency (103050), and Smith-Lemli-Opitz syndrome (SLOS; 270400). Miles et al. (2008) presented an expert-derived consensus measure of dysmorphic features often observed in patients with autism. The goal was to enable clinicians not trained in dysmorphology to use this classification system to identify and further subphenotype patients with autism. The measure includes 12 body areas that can be scored to arrive at a determination of dysmorphic or nondysmorphic. The body areas include stature, hair growth pattern, ear structure and placement, nose size, facial structure, philtrum, mouth and lips, teeth, hands, fingers and thumbs, nails, and feet. The model performed with 81 to 82% sensitivity and 95 to 99% specificity.
Gauthier et al. (2011) identified a heterozygous 1-bp deletion (2733delT) in the NRXN2 gene (600566) on chromosome 11q13 in a boy of European ancestry with autism spectrum disorder. The mutation resulted in premature termination. In vitro functional expression ... Gauthier et al. (2011) identified a heterozygous 1-bp deletion (2733delT) in the NRXN2 gene (600566) on chromosome 11q13 in a boy of European ancestry with autism spectrum disorder. The mutation resulted in premature termination. In vitro functional expression studies in COS-7 cells showed that the mutant protein was unable to bind its usual partners, and in vitro studies in neuronal culture showed a loss of synaptogenic activity with lack of clustering of postsynaptic components. The findings were consistent with a loss of function. The mutation was inherited from the patient's father, who had severe language delay. A maternal aunt of the father's had schizophrenia, but DNA was not available from her. The patient was identified from a cohort of 142 patients with autism who were screened for mutations in the NRXN1 (600565), NRXN2, and NRXN3 genes. Sanders et al. (2012) used whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sib pairs, to demonstrate that highly disruptive nonsense and splice site de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, they demonstrated that multiple independent de novo single-nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there was a single instance in probands, and none in sibs, in which 2 independent nonsense variants disrupt the same gene, SCN2A (182390). Sanders et al. (2012) combined all de novo events in their sample with those identified in the study of O'Roak et al. (2012) and observed from a total of 414 probands 2 additional genes carrying 2 highly disruptive mutations each, KATNAL2 (614697) and CHD8 (610528). O'Roak et al. (2012) performed whole-exome sequencing for parent-child trios exhibiting sporadic autism spectrum disorders, including 189 new trios and 20 that were previously reported (O'Roak et al., 2011). In addition, O'Roak et al. (2012) sequenced the exomes of 50 unaffected sibs corresponding to 31 of the new and 19 of the previously reported trios, for a total of 677 individual exomes from 209 families. O'Roak et al. (2012) showed that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop autism spectrum disorders. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations mapped to a highly interconnected beta-catenin (116806)/chromatin remodeling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in 2 genes: CHD8 and NTNG1. Mutation screening of 6 candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B (138252), LAMC3 (604349), and SCN1A (182389). Combined with copy number data, these data indicated extreme locus heterogeneity in ASD. O'Roak et al. (2012) concluded that their analysis predicted extreme locus heterogeneity underlying the genetic etiology of autism. Under a strict sporadic disorder-de novo mutation model, if 20 to 30% of the de novo point mutations are considered to be pathogenic, they could estimate between 384 and 821 loci. Furthermore, 1 individual inherited 3 rare gene disruptive CNVs and carried 2 de novo truncating mutations. Neale et al. (2012) assessed the role of de novo mutations in autism spectrum disorders by sequencing the exomes of ASD cases and their parents (175 trios). Fewer than half of the cases (46.3%) carried a missense or nonsense de novo variant, and the overall rate of mutation was only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harbored de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating data indicated that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily sufficient for disease). Neale et al. (2012) concluded that their results supported polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provided strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors. O'Roak et al. (2012) developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, O'Roak et al. (2012) captured and sequenced 44 candidate genes in 2,446 ASD probands, and discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. O'Roak et al. (2012) estimated that recurrent disruptive mutations in 6 genes--CHD8, DYRK1A (600855), GRIN2B, TBR1 (604616), PTEN (601728), and TBL1XR1 (608628)--may contribute to 1% of sporadic autism spectrum disorders. O'Roak et al. (2012) concluded that their data supported associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicated the importance of a beta-catenin/chromatin-remodeling network to ASD etiology.
Smalley (1997) reported that autism has a population prevalence of approximately 4 to 5 in 10,000 with a male to female ratio of 4 to 1.
In a review of 20 studies on autism published between ... Smalley (1997) reported that autism has a population prevalence of approximately 4 to 5 in 10,000 with a male to female ratio of 4 to 1. In a review of 20 studies on autism published between 1966 and 1997, Gillberg and Wing (1999) determined that autism is considerably more common than previously believed. The early studies yielded prevalence rates of under 0.5 per 1,000 children, whereas the later studies showed a mean rate of about 1 in 1,000. Children born after 1970 had a much higher rate than those born before 1970. Bertrand et al. (2001) performed a prevalence study of autism spectrum disorders in Brick Township, New Jersey. There were 6.7 cases per 1,000 children, aged 3 to 10 years, in 1998. The prevalence for children whose condition met full diagnostic criteria for autistic disorder was 4.0 cases per 1,000 children, and the prevalence for PDD-not otherwise specified (NOS) and Asperger syndrome was 2.7 cases per 1,000 children. In a review, Jones et al. (2008) noted that the significant increase in the frequency with which autism spectrum disorders is diagnosed, from 4 per 10,000 in 1950 to 40 to 60 per 10,000 as of 2008, results from greater awareness, availability of services, and changes in diagnostic criteria to include a broader spectrum of neurodevelopmental disorders, among others.