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Page 252 Dana et al. J Transl Genet Genom 2020;4:251-62 I http://dx.doi.org/10.20517/jtgg.2020.25

CHARACTERISTICS AND GENETIC BACKGROUND OF AUTISM SPECTRUM DISORDERS
Autism spectrum disorders (ASD) is a lifelong disorder with onset during childhood which is characterized
by rigidity and ritualistic/repetitive patterns of interest disturbing various brain regions including
[1]
prefrontal, hippocampal, cerebellar, and striatal and other midbrain regions . In approximately half
of the cases, ASD is associated with intellectual disability (ID), comorbidity with other conditions
including epilepsy, attention-deficit hyperactivity disorder, anxiety, depression, tics, sleep disorders, and
[2-7]
gastrointestinal problems . ASD prevalence and diagnostic rates have risen significantly over the past two
[8,9]
decades reaching 1.0%-2.5%, with a male to female ratio of 4 to 1 . The reasons for sex discrepancy are
not yet clearly understood . Some studies argue that the differential expressions of ASD between sexes
[8,9]
may result in an underdiagnosis of females because male patients tend to have more external behaviors
such as increased repetitive behavior or aggression while female patients show more internal behaviors
including depression, anxiety, and other emotional symptoms [2,10] . Males and females show similar levels
of depression in childhood, but those levels diverge in adolescence, becoming dramatically greater in
[11]
females . During adolescence, females of autism are associated with high comorbidity including tic and
eating disorders, high incidence of suicide, and high rates of other medical problems . Additionally, ASD
[12]
is diagnosed later in life in girls than in boys and some studies have reported that ASD symptoms may
be milder in females or are masked by the occurrence of other comorbidities, such as depression, ID, or
anxiety. Girls are expected to be more verbal and social by society than boys, and they can be more skilled
at hiding social deficits .
[13]
ASD was considered a complex disorder that includes the complex interaction of genetic, epigenetic,
and environmental factors which may lead to the alteration of brain structures and functions [14-16] .
Clinical heterogeneity is the characteristic of ASD cases, and this heterogeneity is present at different
levels of analysis such as genetics, neural systems, cognition, development, and behavior, as well as in
clinical features from response to treatment . Despite the current technological advances, the etiology
[17]
of autism is still unknown and great efforts are being made to understand the nature of autism and its
[18]
associated molecular pathways . Rett’s syndrome, fragile X syndrome, and tuberous sclerosis (TS) are
classified as syndromic ASD. Patients with syndromic autism have chromosome structure abnormalities
or mutations . These syndromes have a unique single gene mutation which is linked to the synaptic
[16]
[19]
protein called as mammalian target of rapamycin (mTOR) . mTOR is a critical protein responsible for
dendritic plasticity and cell survival. mTOR may be implicated in disrupted cell signaling in idiopathic
ASD. A unique gene has not been identified to cause idiopathic autism. Several candidate genes have
been identified for autism [20-22] . Idiopathic autism that is not associated with a syndrome is called classic
[16]
autism. It is estimated that rare genetic variants are responsible for about 10%-30% ASD cases . Autism
has a strong genetic basis with a complex transmission model that is thought to be the result of at least
1000 interacting genes [23,24] . These genes are associated with pathways such as cell growth and proliferation,
synaptic activity and organization, transcription regulation, ubiquitination, chromatin rearrangement,
[25]
protein synthesis, and transcription factors [Figure 1]. Several autism susceptibility genes including
NRXN1, NLGN3, NLGN4, GABRB3, SHANK2, SHANK3, SCN1A, and CNTNAP2 have been identified by
sequencing technologies [1,4,15] . Dysregulation of transforming growth factor β, bone morphogenetic protein
(BMP), WNT/β-catenin, fibroblast growth factor (FGF), sonic hedgehog (SHH), and retinoic acid (RA)
[1]
signaling pathways have been implicated in the pathogenesis of ASD .

Several alterations have been detected in both the macro and microscopic structures of the brain in
autism. In most ASD cases, the cerebral cortex is qualitatively similar to typically developing subjects in
its general organization [26-29] . Abnormalities of brain development may contribute to the autism pathology.
[30]
Neuritogenesis may also represent the structural basis of autism pathology . Abnormal functioning and
changes of the cerebellum have been revealed in the postmortem brains of autism patients. There is a
decrease in the number of Purkinje cells in the cerebellum . Neuropsychiatric developmental disorders
[31]