Etiology of ASD

Etiology of ASD

1.     Prevalence of autism

2.     Is the “epidemic” of autism really on the increase?

3.     Etiology

a). Genetics

i. Chromosomal abnormalities

ii. Copy Number Variants (CNV`s)

iii. Single gene disorders

iv. Syndromic and Other genetic disorders

v. Overlapping genetic similarities between etiology of autism & ID/epilepsy

vi. Theories behind genetics and autism

b). Environmental factors

c). Genes & Environment

d). Male: Female ratio in relation to the etiology of autism

e). Importance of learning about the etiology of autism


Definitions of some commonly used terms in relation to genetics

  • Genes: A gene is a unit of heredity in a living organism. Made up of DNA & RNA. (Wikipedia)
  • Single Gene Disorder – These disorders manifest as a result of a mutation that causes an alteration in the protein product of a single gene. (30)
  • Chromosome: Is made up of thousands of genes. Humans have 23 pairs.
  • Chromosome Abnormalities – These abnormalities involve entire alterations/duplications/deletions of entire chromosomes. (30)
  • Copy Number Variations (CNV) - Random submicroscopic deletions & duplications found in genes. (1)
  • Loci/locus- The specific location of a gene or DNA sequence on a chromosome. (Wikipedia)
  • Allele – A variation of the DNA sequence at a given locus. (Wikipedia)
  • De novo – alteration in a gene present for the first time. (NIH)
  • Penetrance – This is the frequency with which an individual who carries an allele/gene for a specific disorder will show the manifestation of it. (19)
  • Dysmorphic – Is a recognizable structural or facial abnormality. (19)
  • Neuroligin – This is a postsynaptic cell adhesion molecule that plays a vital role in balancing inhibitory and excitatory neurotransmission. (19)
  • Morphogenesis – is the biological process of an organism beginning to develop it`s shape. (Wikipedia)
  • Epigenesis – Changes in the expression of a gene that is caused by anything other than its underlying DNA sequence. (Wikipedia)

1.     Prevalence of autism

i. The recent prevalence rate of autism is 1 in 150 children. This would mean that almost 27,000 children with autism are born annually in the US, at a birth rate of 4 million. (2)

ii. To break down the prevalence rate further, a recent study indicated that 1/91 3-17 year olds (3) and 1/110 8 year (4) old children have a diagnosis of autism.  

iii. Autism is 4 times more common in males than in females. (5)

iv. Prevalence of autism has increased by 5-10 fold in the last 20 years. (2)

v. According to the Center for Disease Control (2009) autism is considered the second most common developmental disorder following mental retardation. (42)


2.     Is the “epidemic” of autism really on the increase?

i. It is unclear whether the true prevalence of ASD has increased. Or whether this increase could be attributed to increased awareness, broadening diagnostic criteria and improved early identification. (2), (1).

ii. The increase in ASD diagnosis in recent years has also seen a decrease in the diagnosis of mental retardation (MR). (2)

iii. Chakrabarti & Fombonne (2005) found that in recent years 30% of children with PDD also received a diagnosis of MR as compared to 70% of children being diagnosed with MR previously. (6)

iv. Previous epidemiological studies on autism did not consider children with milder language impairments & less aggressive behaviors as part of ASD. (1)

v. Earlier diagnosis age & inclusion of children with milder symptoms of ASD has accounted for 2/3rds of the increased prevalence rates. (1)


a).  Genetics

I. Genetic causes can be identified in about 20-25% of children diagnosed with ASD. Etiology for the remaining 75-80% is unknown. (1)

II. ASD is one of the most heritable neuropsychiatric disorders and research conducted so far indicates a complex genetic basis. (21)

III. Many genetic studies have been conducted but no significant findings have been replicated so far. (7)

IV. The heterogeneous nature of autism accounts for the complex nature of it`s genetic makeup. (9) (19)

V. Approximately 103 disease genes and 44 genomic loci have been identified in association with autism. (5)

VI. Autism could manifest from possibly hundreds of genetic & genomic disorders. (5)

VII. It is understood that autism has a strong genetic basis due to reoccurrence among twins and family. Usually found to co-occur with chromosomal disorders and other genetic syndromes. (5) Similar traits of autism were found among twin and siblings studies. (8)

VIII. Studies have shown that there is a high monozygotic twin concordance rate of  73-95%, high heritability (90% as estimated from twin studies) and a 5/100-6/100 chance of occurrence among siblings. (10) (11)

IX. Most genetic information about autism emerges from known genetic disorders that are associated with the behavioral phenotype of autism. (1)


i. Chromosomal abnormalities

I.  The search for genetics has been centered on genetic mutations & copy number variants. (12).

II. Cytogenetically identifiable chromosomal abnormalities have been found in approximately 7% of individuals with ASD. (13)

III. Chromosomal abnormalities were found particularly in individuals with dysmorphic features & low functioning autism. (14)

IV. Both familial cytogenetic abnormalities & de novo have been associated with ASD. (15)

V. Duplications/alterations of the Angelmann/Prader area are the most commonly seen chromosomal abnormalities in ASD. (1).

VI. Some commonly seen chromosomal mutations associated with ASD, inverted duplications of chromosome15, duplication of 17q11.2, microduplication of 22q11.2 and deletion of 2q37. (16)

ii. Copy Number Variations (CNV)

I. CNV`s are rare, structured, spontaneous variations that could sometimes occur in DNA. (17 & others)

II. CNV`s along with de novo occurrences have been reported in 5-10% of individuals with ASD. (17 & others)

III. Children with ASD are 4 times more likely than their siblings to have CNV`s.

IV. CNV`s could affect many loci. (17 & others)

V. CNV`s have been found in others neuropsychiatric disorders such as, epilepsy, intellectual disability, schizophrenia, ADHD & bipolar disorder. CNV`s may carry increased risks at developing these disorders. (5)(1)

VI. Studies have found that unaffected parents and family members maybe carrying de novo associated with ASD. (54)

VII. Researchers found that females with autism had an increased number of CNV`s involving more number of genes, as compared to boys with autism. This could be an indication that females have a higher tolerance in their genome to CNV`s than boys. Therefore, females would need a higher number of CNV`s to cause autism. (54)

VIII. Miles (2011) proposed the second hit model, which suggests that de novo mutations associated with ASD, along with other risk conferring variants could act as a predisposition to this disorder. (1)

iii. Single gene disorders (9)

I. Features of autism have been identified in a number of single gene disorders. These are known as “autism of known etiology”. (1)

II. 10-15% of individuals with ASD present with single gene mutations. (22)

III. Many children with ASD also present with some form of learning disability, genetic disorders associated with learning disability have also been linked to ASD. (9)


iv. Table 1: Syndromic & other genetic disorders associated with ASD (1)

(These could be caused by chromosomal abnormalities or single gene disorders)



Associated anomaly

Reason to be linked with ASD

Syndromic Disorders

§  Fragile X syndrome




X linked dominant disorder




- Fragile X has been found in about 2% of individuals with ASD. (5)

- Fragile X is the most common cause of inherited learning disability.

- More prevalent in males. Prevalence rate of autism among males having Fragile X ranges from 1.5/100 to 3.3/100.

- Loesch et al found that the level of the fragile X protein FMRP (Familial Mental Retardation Protein) correlated with the degree of autism on the Autism Diagnostic Observation Scale (ADOS). (20)

- There is a significant overlap between behaviors in ASD and fragile X. (1)

§  Rett Syndrome

X linked dominant disorder

- The only ASD disorder that has a specific genetic etiology. (1)

- Rett`s is caused by a mutation in the gene encoding protein methyl-CpG-binding protein 2 (MeCP2)

- These mutations have been reported in 1% of individuals with ASD.

- In classic cases of Rett`s, individuals develop normally until they display developmental arrest/regression and features of autism start to manifest.

§  Angelman/Prader-Willi Syndrome (PWS)

X linked recessive disorder

- Impairments in chromosome 15q11 to q13 could manifest either of these two syndromes.

- Chromosomal deletions on the paternal chromosome cause Prader-Willi, and deletions on the maternal cause Angelman Syndrome. Increased occurrence of ASD with Prader-Willi.

- ASD has been reported in 23% of cases in Angelman/Prader-Willi. (23)

- ASD has been diagnosed in 25/100 individuals who present with this syndrome.

- Studies show that individuals with PWS have repetitive behaviors and social impairments similar to ASD. Characteristic features in Angelman include being non-verbal, impaired use of non-verbal communication, attention deficits, hyperactivity and motor delays which are also similar to ASD.

- Autism is considered a co-morbidity in this disorder

§  Inv dup(15) or idic(15) syndrome

Related to 15q chromosome

- It is a rare neurogenic disorder exhibiting characteristics of autism.

§  Down Syndrome (DS)

Anomaly in Trisomy 21

- The frequency of ASD occurring in DS has been reported to be 1/100 to 11/100.

- Autism is 10 times more likely to occur in children with DS, than in the general population.

- ASD manifests as a behavioral phenomenon, displaying behaviors such as anxiety, stereotypical movements, social withdrawal and disruptive behavior.

§  Timothy Syndrome (TS)


Rare autosomal dominant disorder

- This is a rare syndrome.

- Splawsi  et al found similarities between ASD and Timothy Syndrome. They stated that individuals with TS met the criteria for ASD. (24) (25)

- In TS, autism manifests along with congenital night blindness and mutations in CACNA1H. This indicates that abnormalities in ion channel function could pose as risk factors for autism. (1)

§  Tuberous Sclerosis Complex (TSC)

Rare autosomal dominant disorder

- Prevalence of TSC in the ASD population is 1/100 to 4/100, features of autism are present in 25/100 to 5/10 individuals with autism.

- Incidence of autism in TSC does not differ between sexes.

§  Turner Syndrome

Associated with X chromosome and it`s variants.

- Associated with increased risk of ASD.

- A study conducted found 5/150 (3.3%) females with Turner Syndrome have ASD.

§  Klinefelter`s Syndrome (XXY)

Have an extra X chromosome

- Individuals with Klinefelter`s syndrome have been identified with ASD.

- A study done by Bishop et al (2010) have reported ASD traits in 48% (15/31) individuals with KS. (26)

§  Smith-Magenis Syndrome (SMS)

Anomaly in chromosome 17p11.2

- Some cases of SMS have been reported as meeting the diagnostic criteria for autism.

- A study done by Hicks et al (2008) reported that 90% of individuals (18/20) with SMS had ASD. (27)

§  Duchene Muscular Dystrophy

X linked recessive disorder

- Caused by a mutation in the gene that codes the protein dystrophin

- A questionnaire-based study done by Hendriksen & Vles found that 3.1/100 individuals had ASD. (28)

§  Developmental Syndromes of unknown etiology


- Moebius Syndrome: Causes unilateral or bilateral paralysis of the 6th and 7th cranial nerves. A study found that Moebius occurs in individuals with ASD along with mental retardation. (33)

- Landau Kleffner: A small number of children with ASD have been diagnosed with LK.

- These children develop sudden or gradual language regression. (34)

Other genetic disorders (some)

·      NLGN3, NLGN4, NRXN1

Anomalies in neuroligin genes




- 1/100 Individuals with autism have been found to have mutations in the neuroligin genes.

- Characteristics associated with these mutations are regression resulting in loss of social and verbal milestones.

·      SHANK3 gene

- SHANK proteins play a role in the development of language and social communication.

- Research shows that mutations in this gene could result in ASD characterized by impairments in social and verbal skills.

·      PTEN gene

- Herman et al stated that mutations in this gene resulted in ASD manifesting with macrocephaly. (29)

·      More

reasons as to why researchers believe that impairments in protein synthesis related genes (some mentioned above) maybe the cause for ASD.

- Evidence suggests that impairments in synaptic protein synthesis maybe the reason that individuals exhibiting the autism phenotype sometimes present with cognitive and savant abilities. (22)

- These mutations that directly affect the synaptic structure in ASD are rare. (22)

- A number of single gene mutations associated with autism may also act as negative regulators of protein synthesis. (e.g. – Fragile X, Angelman). (22)

- Researchers have speculated that excessive synaptic capture could lead to enhanced long term memory formation which is a feature found in individuals with ASD who have savant abilities. This excessive synaptic structure could cause generalized cognitive impairments along with enhanced memory skills. (22)

§  Mitochondrial  Disorders

·      Phenylketoneuria (PKU)

- A study done on PKU found that 68 people with PKU who were diagnosed & treated for PKU early did not meet criteria for autism, whereas 5.7% of individuals with PKU with late diagnosis met the criteria for autism.  (31)

·      Creatine deficiency Syndrome

- Three different errors of Creatine metabolism have been described with symptoms of autism. (1)

- Prevalence of Creatine deficiency in ASD is low. (1)

·    Smith-Lemli-Opitz Syndrome

- A study found that ¾ of children with this syndrome met the criteria for ASD. (32)

§  Metabolic Disorders


- Ceylan et al (2011) reported that metabolic disorders could be associated with symptoms of autism, based on a single case study. (43)

- These metabolic disorders manifesting autism were genetic in origin. (43)

v. Table 2: Overlapping genetic similarities between autism and intellectual disability; and autism and epilepsy.

Autism & Intellectual Disability (ID)


Autism & Epilepsy

I. Similar genes & loci have been found in both autism & ID. This is an indicator that both these neurodevelopmental disorders could share common genetic basis. (5)

II. 70% of individuals who have ASD have ID too. (35)

III. Fragile X is the most commonly occurring single gene mutation associated with ASD and ID. (5)

IV. Similar to autism, ID too is a commonly occurring heterogeneous disorder. (5)

V. Large number of x-linked forms account for the 30% higher prevalence of ID in males than females (36). The higher occurrence in males is similar to ASD.

VI. Genes identified to cause non-syndromic ID have also been associated with the etiology of non-syndromic ASD. (5)

I. Baird et al (2006) found that epilepsy occurs in 25% of persons with ASD. (35)

II. Several genes associated with the cause of epilepsy could also result in ASD & epilepsy. (5)

vi. Theories behind genetics and autism.

I.               Miles et al (2005) wanted to distinguish between complex vs. essential autism. (18)

II.             Table 3: Complex vs. essential autism (18)

Complex autism


Essential autism

1. Observed to have dysmorphology and/or microcephaly. Both dysmorphology and microcephaly are early indicators of abnormal morphogenesis.

1. Absence of dysmorphology

2. Lower male to female ratio

2. More likely to be male

3. Lower sibling recurrence risk

3. Higher sibling recurrence risk

4. Associated with poorer prognosis

4. Siblings of individuals with essential autism are more likely to have mild autistic traits as compared to siblings of complex autism.

5. Approximately 20-30% of individuals diagnosed with ASD have complex autism.

5. Greater family history of autism and disorders such as alcoholism and depression.

6. 25% of children with complex autism are diagnosed with an associated syndrome or chromosomal disorder


III.           Trying to distinguish between complex and essential autism was one of the earliest attempts to separate etiologic heterogeneity within autism itself. (1)

IV.            Geschwind & Levitt  (2007) proposed that there maybe a high number of penetrant autism causing genes that could be present in a given family. (37)

V.              Beaudet (2007) and others proposed that there maybe two classes of autism. Class one which maybe the more common of the two is that autism is genetic but not heritable. These cases are caused from new mutations or de novo CNV`s that maybe occurring as a result of increased paternal age. The second class maybe caused due to familial mutations, and these cause recurrences among siblings. (38) (39) (40)

VI.            This suggests that both genetic changes and familial inherited mutations play a role in the etiology of autism. (1)

VII.          Another on going debate is the common disease common variant (CD/RV) vs. common disease common variant (CD/CV) causing autism. (1)

VIII.        CD/RV is that a number of rare mutations cause autism. Autism genes identified from isolated families and from rare CNV`s support this hypothesis. (41)

IX.            CD/CV is that a few common mutations in alleles cause the genetic variations, which result in autism. Constantino et al suggest that common variants do play a role in the determination of behaviors related to autism. (1)


b). Environmental factors and autism

i. Epidemiological studies in ASD have not been successful in pin pointing an exact genetic causal factor. The focus of research in recent years has shifted from solely being on genetics, to researchers believing that the environment plays a role as well. (44)

ii. Deth et al (2008) stated that genetics alone can `t explain the rapid increase in the prevalence rates of autism. They concluded that the environment must also play a role in etiology. (45)

iii. Heavy metals – Exposure to heavy metals being a causal agent has been a topic of debate, specifically mercury, which is recognized as a neurotoxin. (46)

iv. Researchers have found the incidence of autism is higher in areas that have increased mercury and lead levels in the air. (47)

v. Symptoms of autism have also been reported in some cases of infantile mercury poisoning. (48)

vi. Exposure in utero to substances such as valproic acid, cadmium, thalidomide & misoprostol are recognized as causing ASD. (1)

vii. Children in utero who were exposed to antiepileptic drugs were 7 times more likely than the general population to develop autism. (49)

viii. Exposure to folic acid antagonists during the prenatal period is also associated with increased risks of developing autism and autistic traits. (50) (51) (52)

ix. Schmidt et al (2011) reported that prenatal vitamin use during the 3 months before pregnancy to 1 month after time period, helped reduce the chances of having a child with autism. (Reduced the odds of autism by 40% for those who took prenatal supplements at least 4 times per week.) (53)

c). Genes & Environment

i.                Schmidt et al (2011) reported that common genetic variations for ASD may exist, but these variations may manifest only in a susceptible group of the population. (53)

ii.              Deth et al (2008) presented their hypothesis, which is that genetics and environment factors together manifest the risks for autism. (45)

iii.             There could be many genes and environmental factors that could lead to autism. Several loci have been found that possibly contribute to the phenotype. Several variants in genes or CNV`s have also been discovered in relation to ASD. (55)

Not all children with these predisposing genes develop autism. This is a good indicator that genetic alterations are just a predisposing factor to autism and not necessarily a cause by themselves. (55)

iv.             Research that has been done on monozygotic twins has been inconsistent and has found less than 100% agreement in traits, leading researchers to believe that autism is not completely dependent on genetics. This suggests interactions between factors such as the environment and susceptible genes. (61)

v.              Certain environmental factors could create toxins or stress in genetically susceptible individuals causing the manifestation of autism or autism like symptoms. They believed that the environment alone, or genetics alone failed to have this effect. It had to be a combination of environmental exposure triggering something in an already genetically susceptible individual. (45)

vi.             Environmental exposures can affect the neurodevelopment of children in different ways. They could be affected either through direct toxicity, or cause mutations in genes or by changing developing cells, which in turn makes them susceptible to environmental agents. (12)

vii.           There has not been much research involving both genetics and environment together playing a role in ASD. Most research has been done on either one or the other area. (12)

viii.          Specific theories about genes & the environment,


I.               A study conducted stated that anti-fetal brain antibodies, which maybe present in the blood circulation of mothers, could in combination with genetic susceptibility cause an effect on neurodevelopment that may lead to autism. (56)

II.             Maternal infections could cause impaired immunological development in the brain, which could lead to neurodevelopmental disorders like autism. (57)

III.           Children with autism have been known to have mutations in the enzyme MTHFR. If pregnant women don`t supplement their diets with folic acid to compensate for the mutation in the enzyme, there could be neurological regression and increased risk for autism. (46)

IV.            Cui et al (2007) have found that Vitamin D is important for neural development (58). However, decreased exposure to sun in the last 20 years due to the American Medical Association (1989) warning about the risks of sun exposure causing cancer has also coincided with the increased prevalence rate of autism (59). Abnormalities in immune functions have been found in individuals with autism that are very similar to those seen with Vitamin D deficiency. (60)

V.              Exposure to heavy metals specifically mercury could be a cause for autism. Researchers have found that on average children with autism have, twice the level of mercury in their bodies as their non-autistic peers. This could be due to children with autism having difficulty excreting mercury and other heavy metals from their bodies. (46)

VI.            Pre-natal Vitamins – A study by Schmidt et al (2011) found that maternal periconceptual prenatal vitamin intake resulted in reduced risks of autism. They also found that the combination of certain gene variations with no intake of prenatal vitamins during the periconceptual prenatal period resulted in significantly higher risks for autism. (62)

VII.          Prenatal vitamins contain iron, Vitamin B6, B12 and folic acid among others. (62)

VIII.        Children with autism and their mothers were found to have impaired methylation when compared to typically developing children and their mothers. (62)

IX.            Periconceptual prenatal vitamins could protect against autism and other neural tube defects by enhancing the methylation mechanism. (62)

X.              This study also found that children with COMT472AA gene in combination with unsupplemented mothers resulted in increased susceptibility of a child to autism.  This study also found that COMT472G>A in combination with environmental factors increases genetic susceptibility to autism. (62)

XI.            A study done on increased paternal age found that with advanced age, an increased number of de novo mutations could occur (64). Children with autism have been found to have an increased number of de novo CNV`s (63). The study found that de novo mutations in combination with exposure over time to various environmental toxins could cause germline alterations in older men. No definitive conclusion could be drawn but the study hypothesized that higher paternal age along with environmental and epigenetic changes could result in a child being born with ASD. (64)


d). Male to female ratio with regard to etiology

i.       Many of the genetic syndromes related to autism occur as a result of impairments in the X chromosome. Along with this the methyl-CPG-binding protein mecp2, which has been identified as a causal factor in individuals with autism is X-linked (46). Therefore, since males only have 1 X chromosome (XY) they would be worse affected by a mutation in the X chromosome than females.

ii. Researchers have found that estrogen has the capacity to increase neural and calcitrol levels in the body, where as testosterone did not (65). Therefore, Cannell (2008) found it maybe possible that estrogen shields the female brain from experiencing calcitrol deficiencies, which may possibly be reducing the risks of autism in females. (66)

iii. A study also found that females with autism had an increased number of CNV`s involving more number of genes, as compared to boys with autism. This could be an indication that females have a higher tolerance in their genome to CNV`s than boys, thereby not being as vulnerable to CNV`s as boys. Therefore, females would need a higher number of CNV`s to cause autism. (54)


e). Importance of knowing and understanding the etiology of autism

i. Although there is a lot of information regarding genetics with regards to autism, there is still an immense amount of research that needs to be done on genetics and genetics and the influence of the environment.

ii. Awareness that autism could co-occur with other genetic syndromes and disorders.  


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