The Genetics of Autism

Abstract

ABSTRACT. Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of ϳ3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is ϳ2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affec...

Neonatal serotonin depletion alters behavioral responses to spatial change and novelty

“…(Chugani et al, 1999;Chandana et al, 2005). A serotonergic (5-HT) deficit during cortical development, moreover, is compatible with reports of treatment successes using serotonin uptake blockers as well as with genetic linkage studies suggesting impairments in genes linked to proper serotonin neurotransmission (Cabelli et al, 1995;Klauck et al, 1997;Anderson et al, 2002;Veenstra-VanderWeele et al, 2002;Conroy et al, 2004;Coutinho et al, 2004;McCauley et al, 2004;Muhle et al, 2004;Murphy et al, 2004;Nabi et al, 2004;Coon et al, 2005;Mulder et al, 2005;Scott and Deneris, 2005;Whitaker-Azmitia, 2005). It is interesting in this context to note that a defective serotonergic innervation is also compatible with alterations of brainstem segmentation genes such as engrailed or Hox 2, which have been implicated in autism (Polleux and Lauder, 2004;Bartlett et al, 2005;Benayed et al, 2005).…”

“…Thus, other cognitive-emotional behavioral features might be under the control of sex hormones as well. Substantial sex dimorphism does exist in several disorders that involve 5-HT imbalances, including autism, depression and anxiety disorders (Earls, 1987;Halbreich and Kahn, 2001;Muhle et al, 2004). Serotonin may not have the same saliency in male and female cortical development and later plasticity, rendering each sex differentially susceptible to 5-HT imbalances in various brain regions.…”

Modeling early cortical serotonergic deficits in autism

“…With the exception of the socially transmitted food preference task, where food consumption was impaired in both sexes, male neonatally 5,7-DHT-lesioned male mice were affected uniquely or more markedly than female lesioned mice. This may be highly relevant in regards to autism where, by most accounts, four times as many males as females are diagnosed [87,107,118,126]. Our own developmental observations in male and female mice [31] together with the data from Chugani's group [27,28] suggest that magnitude of an early postnatal peak or elevation in cortical serotonergic innervation is sex specific.…”

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

“…4,7,8 It has been estimated that 10-15 genes may be implicated in the regulation of the complex genetic risk of autism-spectrum disorders. [9][10][11][12] However, the risk is not conferred in a Mendelian fashion and identification of these genes has been hampered further by the probably small population effect sizes of each of them, and the lack of clear pathophysiology hints to suggest particularly strong candidate genes. Therefore, the typical approach to-date has been the performance of genome scans.…”