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Genetics of Autism Spectrum Disorders

Background

Autism spectrum disorders (ASDs) are characterized by impaired socialization, reduced communication, and restricted, repetitive, or stereotyped activities and interests.
As defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), ASD encompasses the previous manual’s autistic disorder (autism), Asperger disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified.
 ASD is characterized by the following: (1) deficits in social communication and social interaction and (2) restricted repetitive behaviors, interests, and activities (RRBs). These symptoms are present from early childhood and limit or impair everyday functioning. Both components are required for diagnosis of ASD. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet the criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder.

The symptoms of ASDs typically are present before 3 years of age and often are accompanied by abnormalities in cognitive functioning, learning, attention, and sensory processing.
ASDs are associated with numerous comorbidities and disabling symptoms, such as aggression and self-injurious behaviors, for which behavioral and psychopharmacologic interventions are the mainstay of treatment.
There is a well-defined increased prevalence in males, with an affected male–to–affected female ratio of approximately 4:1.

Although ASDs were once considered rare, they are common today, and their prevalence has been dramatically increasing.
On the basis of data from medical records of children who had been diagnosed with or showed signs of ASDs across the United States, the overall US prevalence has been estimated to be approximately 1%, or about 1 in every 110 children.

According to data from monozygotic twin studies, ASDs have an estimated heritability of more than 90%.
Patients with various Mendelian or monogenic diseases—such as Rett syndrome (defective MECP2), fragile X syndrome (defective FMR1), neurofibromatosis 1 (defective NF1), and tuberous sclerosis (defective TSC1 or TSC2)—display features characteristic of the ASDs,
but these causes of ASDs are rare.

The vast majority of family studies suggest that the ASDs do not segregate as a simple Mendelian disorder but, rather, display patterns consistent with a complex trait.
Coupled with this genetic heterogeneity is considerable clinical heterogeneity, as illustrated by substantial differences in the extent and quality of symptoms.

Genome-wide association studies (GWAS) have implicated the region on chromosome 5p14.1 between CDH9 and CDH10 as the first potential common genetic risk factor in Caucasian populations.
However, resolving the GWAS signal from single nucleotide polymorphisms across large genomic regions to specific causal mutations requires large-scale sequencing; studies using this approach are forthcoming.

Therefore, although ASDs are known to be extremely heritable, their common genetic causes remain largely elusive because of the complex behavioral phenotypes and multigenic etiology of these disorders.

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