• ICCONS, Kavalappara, Shoranur, Palakkad-679523, Kerala (0466) 2224869
  • ICCONS, Pulayanarkotta, Thuruvikkal PO, Trivadrum - 695011, Kerala (0471) 6066061
  • icconssrr@gmail.com

Autism - Genetics of Autism Spectrum Disorders

ASDs are among the most heritable of neurodevelopmental disorders. Family- and twin- based studies have clearly proved the genetic basis of autism. There is a 36-91% chance of identical twins being autistic. Identical twins share the same DNA since they are derived from the same embryo. Fraternal twins on the other hand, share only 50% of their DNA since they come from two different embryos, and there is only 2-4% chance of both being autistic.

As ASDs are among the most heritable of all psychiatric disorders, much effort has been made to elucidate the underlying genetics, to identify the responsible genetic variants and chromosomal abnormalities. However, unlike some of the monogenic disorders which are caused by defects in a single gene, the genetics of autism is very complicated. It is because autism manifests a wide range of symptoms and probably several genes are involved. Owing to this high degree of heterogeneity, none of the known genetic causes of autism account for more than 1% of the ASD cases; a common susceptibility locus has not been reported until now. Therefore, attention has now been shifted to identify the rare variants associated with the disorder.

During the last decade, scientists from all over the world have worked together to trace autism candidate genes. Data has been collected from thousands of autistic families from different populations across the world. Linkage analyses and family-based association studies have resulted in the identification of hundreds of autism candidate genes. The recent evolution of SNP microarray and high-throughput sequencing technologies accompanied by large well-characterized patient cohorts is now leading to a rapidly accumulating pool of well-established genes and loci. This could lead to the emergence new treatment strategies. Genetic diagnostic tests leading to the early detection of this disorder may come up in the near future.


Classic candidate genes: current status

At present, using modern genetic methods, as many as 235 genes associated with autism, with supportive evidence from ≥ 5 independent studies (Autism database- https://gene.sfari.org/autdb/CNVHome.do) (Table-1) have been identified. These genes were identified through single nucleotide polymorphism (SNP) association studies and/or sequencing and/or gene expression analyses. SNPs, which are single base alterations in a DNA sequence, are responsible for much of the genetic variation in the human genome. Genetic association studies can be used to examine whether a particular genetic variant is associated with the disorder. Since most of the associated SNPs are located in the non-translated portions of the genome, their functional impact cannot be determined. However, several functional SNPs, leading to a defective protein, have also been identified in the exonic regions of autistic individuals.

Despite the diversity, ASD patients exhibit similar behavioral and neuronal conditions, although differing in severities and comorbidities. This commonality of neurological phenotypes suggests that the susceptible genes may act through a limited set of pathways (Lanz et al, 2013). Several studies have suggested a role for the genes involved in synaptic assembly, such as the synaptic cell adhesion molecules (CAMs), ion channels, neurotransmitter receptors, and the scaffolding and cytoskeletal proteins that work harmoniously to provide synaptic structural integrity and functionality (Banerjee et al, 2014). Research in the past few years is being focused on the following most important candidate genes of autism.

  • Cell Adhesion Molecules (CAMs)
    1. Neurexins and neuroligins: These are pre- and post-synaptic CAMs respectively. Several studies have reported mutations of these genes in autism (Jamain et al 2003; Yan et al, 2005; Kim et al, 2008; Vaags et al, 2012). Neuroligin-deficient mice display abnormal social and vocal behaviors that resemble ASDs symptoms (Tabuchi et at, 2007). Impairments in social behavior traits have been found in neurexin knockout mice too (Grayton et al, 2013).
    2. Contactins (CNTNs): They have diverse roles in synapse formation and plasticity. Recurrent small deletions and duplications involving CNTN3 and CNTN4 have been reported in several ASD patients (Roohi et al, 2009). Rare mutations have been observed in CNTNAP2, a gene known to be associated with language quantitative traits (Alarcon et al, 2008). Cntnap2 mutant mice revealed deficits in the three core ASD behavioral domains, with hyperactivity and epileptic seizures (Penagarikano et al, 2011). The drug risperidone could reverse some of these behaviors in the mutant mice, opening new avenues for the therapeutic intervention in ASD.
    3. Cadherins and protocadherins (CDH and PCDH): These are a large family of CAMs required for synaptic specificity. CDH18, PCDHA, PCDH10 and PCDH9 have been found to be disrupted in ASD, mental retardation and intellectual disability cases (Marshall et al, 2008; Morrow et al, 2008; Anitha et al, 2013).
  • Ion Channels

    Ion channels are essential mediators of neuron excitability and neurotransmitter release within the central nervous system. Recent data has implicated neuronal excitation alterations in ASD, pointing to a potential role for ion channel proteins in disease susceptibility.

    4. SCN1A and SCN2A are trans-membrane voltage-gated sodium channels. SCN1A has emerged as the most important gene in epilepsy with more than 70% of individuals with epileptic encephalopathy possessing a mutation in this gene (Mulley et al, 2005). Several patients with a mutated gene have been found to exhibit autistic-like behaviours. Loss-of-function mutant mice also exhibit autistic behaviours (Han et al, 2012).
    5. CACNA1C codes for the alpha subunit of voltage-dependent calcium channels. A well known mutation in this gene causes Timothy syndrome; while other genetic variations has been associated with various psychiatric diseases (Lu et al, 2012).
    6. GABRB3 encodes one of the subunit of a chloride channel which serves as the receptor for GABA, a major inhibitory neurotransmitter. Genetic association has been reported in various populations (Menold et al, 2001; Ashley-Koch et al, 2006; Delahanty et al, 2011).
  • Scaffolding Proteins

    Shank family of scaffolding proteins are essential for the synaptic architecture.

    7. SHANK2 and SHANK3: The genetic association of ASD with SHANK family genesis well characterized (Berkel et al, 2012; Sato et al, 2012; Uchino and Waga, 2013).Neurobiological studies of Shank mutations in mice support the general hypothesis of synaptic dysfunction in the pathophysiology of ASD (Jiang and Ehlers, 2013).
  • Neuropeptide Receptors

    The neuropeptides oxytocin and vasopressin are regulators of social cognitive skills (Israel et al, 2008). Polymorphisms in the genes coding for the receptors of these molecules could be relevant to individual differences in mammalian social behaviours.

    8. AVPR1a- Genetic associations and rare variants in the arginine vasopressin receptor gene were reported in several studies (Yirmiya et al, 2006; Yang et al, 2010). 9. OXTR- The oxytocin receptor gene was found to be associated with ASD in a number of independent studies (Wermter et al, 2010; Campbell et al, 2011; Skuse et al, 2014).
  • Signaling Pathways

    Disruption of genes involved in critical signaling cascades often contribute to the development of ASD phenotypes.

    10. The mTOR pathway: The serine/threonine protein kinase, mechanistic target of rapamycin (mTOR), has a pivotal role in synapse formation. The mTOR signaling pathway includes genes such as NF1, PTEN, TSC1, and TSC2; recurrent mutations have been reported in these genes in several cases of autism-like behavioral phenotypes. Inherited or de novo PTEN mutations are one of the most validated causes of autism (O’Roak et al, 2012a). Mutant mice showed deficits in synaptic strength and displayed behavioral deficits common to autism (Xiong et al, 2012).
  • Other Important Candidate Genes
    11. RELN- a serine protease that plays a critical role in neuronal migration during brain development. Several studies have shown genetic associations (Serajee et al, 2006; Fu et al, 2013); rare mutations were also reported (Neale et al, 2012). 12. MET- mediated signaling has been implicated in multiple aspects of neocortical and cerebellar neuronal growth and maturation. Number of positive associations have reported (Campbell et al, 2006; Thanseem et al, 2010; Plummer et al, 2013)

Copy Number Variation (CNV) Studies-Recent Progress

CNVs are the most common structural variations found in the human genome and represent a major part of genetic variability. It can be vary in size from a few kilo bases to several mega bases and may affect the information coded for the relevant genomic region. CNVs could affect the phenotype though the mechanism of “dosage sensitivity”, though the idea still remains far from established. Copy number gains or losses can alter the expression of critical genes which may leads to partial dysfunction (Iossifov et al, 2012). The genes that are required for the recently acquired human traits of speech and complex social behaviors may be particularly vulnerable. The concept of CNVs as a possible genetic contributor to the development of ASD was emerged, ever since the publication of first CNV based study on autism families (Sebat et al, 2007).Since then, multiple large studies have been performed using different platforms to examine different cohorts. Several novel or rare CNVs, both de novo and inherited, were identified, especially affecting regions like 1q21, 5p15.2, 7q11-13, 15q13.3, 16p11.2, 17p11.2 and 22q11.2 (Malhotra and Sebat, 2012; Prasad et al, 2012). A list of recurrent CNVs associated with the disorder identified in multiple studies across various populations is shown in Table -2 (extracted from SFARI gene database). De novo events were often more deleterious than inherited variations (Veltman and Brunner, 2012). The reported CNVs in autism are often enriched in genes with important functions in the nervous system like post synaptic translational regulation, neuronal cell adhesion, neuronal activity modulation and excitatory and inhibitory function imbalance (Devlin and Scherer, 2012). Functional impact of CNVs were recently been investigated by studying the expression profile of genes within the rare de novo CNVs (Luo et al, 2012). Genes which are involved in neural-related pathways were found to be mis-expressed.

Most recent data supports an oligogenic model in which severity of the neurodevelopmental disease increases with the increasing CNV burden (Coe et al, 2012). Smaller CNVs with a median size of 18 kb which are often not detected by SNP microarrays were recently analyzed using exome sequence data (Krumm et al, 2013). It was found that probands inherited more CNVs than their siblings and that their CNVs affected more number of genes. A novel study focused on genomic ‘hotspot’ areas which are prone to recurrent rearrangements provided evidence for a phenotypic dependence on the size of the CNV (Girirajan et al, 2013a). As the size of deletions increases, nonverbal IQ significantly decreases, but there was no impact on autism severity; and as the size of the duplication increases, autism severity significantly increases but nonverbal IQ was not affected. It was proposed that this increased duplication load in genomic hotspot areas predisposes to autism (Girirajan et al, 2013b).


Exome Sequencing-Unmasking Rare Variants

Though human genome consists of nearly 3 billion nucleotides, only a small portion (around 1.5%) of it actually constitutes the exons which are translated into proteins. Instead of sequencing the whole genome which still requires considerable cost and time, it would be an easier and faster strategy to sequence all the protein coding regions of the genome. The “exome” consists of all the exons of the genome and has a total size of only around 38Mb. Exome sequencing involves the targeted capture of exons followed by the high-throughput sequencing of exon-enriched samples using next generation sequencers. Genome-wide interrogation of the protein coding regions is a powerful approach to identify causal variants and candidate genes in individuals and families with a complex genetic disorder.

Over the past three years, several independent groups have conducted whole exome sequencing using non-overlapping ASD samples (Iossifov et al, 2012; Neale et al, 2012; O’Roak et al, 2012b; Sanders et al, 2012; Nava et al, 2012; Michaelson et al, 2012; Yu et al, 2013; Jiang et al, 2013). O’Roak et al, (2012a), using 189 trio families, showed that de novo point mutations are overwhelmingly paternal in origin. Such a paternal bias in de novo point mutations has also been reported by Iossifov et al (2012), during the same period. Several novel genes were identified through these studies as playing a role in liability for ASD. These results further highlight the extreme genetic heterogeneity of ASD, while pointing towards a relatively small number of implicated biological pathways. Many of these de novo mutations identified disrupted genes in neural development and plasticity, chromatin related proteins involved in transcriptional regulation, especially during prenatal brain development (Ben-David and Shifman, 2013).


Disorder Cause Genetic Testing
Down syndrome an extra copy of chromosome 21 Available
Down syndrome an extra copy of chromosome 21 Available
Fragile X syndrome abnormality of FMR1 gene Available
Williams syndrome deletion in chromosome 7 Available
Angleman syndrome deletion of the maternal copy of UBE3A gene on chr 15 Available
Prader-Willi syndrome deletion of the paternal copies of 7 genes on chr 15 Available
Phelan-McDermid syndrome deletion in chromosome 7 Available
Rett syndrome deletions in the long arm of chr 22 Available
Tuberous sclerosis mutations in TSC1 and TSC2 genes Available
Timothy syndrome mutation in CACNA1C gene on chr 16 Available
Smith-Lemli-Optiz syndrome mutation in DHCR7 gene on chr 11 Available
Turner syndrome absence of one X chr in females Available
Klinefelter syndrome an additional X chr in males Available

Genetic Tests for Autism

The high heterogeneity and the absence of common variants make the genetic testing of non-syndromic forms of ASD, which account for around 90% of the cases, very difficult. Still some laboratories and companies are now offering panels or arrays which target several dozens of autism candidate genes.


Future directions

Estimation of the functional consequences of CNVs and rare mutations, and the translation of this knowledge to support clinical decisions towards personalized pharmacological interventions is a real future challenge. Much greater wealth of available data concerning CNVs, rare variants, common variants and gene pathways involved in autism is indeed spearheading this ultimate aim of developing novel pharmaceuticals and tools for early genetic diagnosis. Further, in exploring the genetic landscape of ASDs, we need to broaden our perspective of the etiology to examine the extensive gene-regulatory elements, including epigenetic modifications and non-coding RNAs, which, in turn, are both influenced by the environment.



Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV et al. (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 82: 150–159.

Anitha A1, Thanseem I, Nakamura K, Yamada K, Iwayama Y et al. (2013) Protocadherin α (PCDHA) as a novel susceptibility gene for autism. J Psychiatry Neurosci. 38(3):192-198.

Ashley-Koch AE1, Mei H, Jaworski J, Ma DQ, Ritchie MD et al. (2006) An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder. Ann Hum Genet.70(Pt 3):281-292.

Ben-David E, Shifman S. (2013) Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol Psychiatry 18(10):1054-1056.

Berkel S, Tang W, Treviño M, Vogt M, Obenhaus HA et al. (2012) Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology. Hum Mol Genet. 21(2):344-357.

Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C et al. (2006) A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A.103(45):16834-16839.

Campbell DB, Datta D, Jones ST, Batey Lee E, Sutcliffe JS et al. (2011) Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. J Neurodev Disord. 3(2):101-112.

Coe BP, Girirajan S, Eichler EE. (2012) The genetic variability and commonality of neurodevelopmental disease. Am J Med Genet C Semin Med Genet. 160C(2):118-129.

Delahanty RJ1, Kang JQ, Brune CW, Kistner EO, Courchesne E (2011) Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry 16(1):86-96.

Devlin B, Scherer SW. (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 22(3):229-237.

Fu X, Mei Z, Sun L. (2013) Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population. Genet Mol Biol. 36(4): 486-489.

Girirajan S, Dennis MY, Baker C, Malig M, Coe BP et al. (2013a) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet. 92(2):221-237.

Girirajan S, Johnson RL, Tassone F, Balciuniene J, Katiyar N et al. (2013b) Global increases in both common and rare copy number load associated with autism. Hum Mol Genet. 22(14):2870-2880.

Grayton HM, Missler M, Collier DA, Fernandes C et al. (2013) Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders. PLoS One 8(6):e67114.

Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS et al. (2012) Autistic-like behavior in Scn1a+/− mice and rescue by enhanced GABA- mediated neurotransmission. Nature 489: 385–390.

Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74(2):285-299.

Jamain S, Quach H, Betancur C, Råstam M, Colineaux C et al. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 34(1):27-29.

Jiang YH, Ehlers MD (2013) Modeling autism by SHANK gene mutations in mice. Neuron 78(1):8-27.

Jiang YH, Yuen RK, Jin X, Wang M, Chen N et al. (2013) Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet. 93(2):249-263.

Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ et al. (2008) Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet. 82(1):199-207.

Krumm N, O'Roak BJ, Karakoc E, Mohajeri K, Nelson B et al. (2013) Transmission disequilibrium of small CNVs in simplex autism. Am J Hum Genet. 93(4):595-606.

Lu AT, Dai X, Martinez-Agosto JA, Cantor RM et al. (2012) Support for calcium channel gene defects in autism spectrum disorders. Mol Autism 3(1):18.

Luo R, Sanders SJ, Tian Y, Voineagu I, Huang N et al. (2012) Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. Am J Hum Genet. 91(1):38-55.

Malhotra D, Sebat J. (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148(6):1223-1241.

Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 82: 477–488.

Menold MM1, Shao Y, Wolpert CM, Donnelly SL, Raiford KL (2001) Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. J Neurogenet. 15(3-4):245-259.

Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D et al. (2012) Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151(7):1431-1442.

Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y et al. (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321: 218–223.

Mulley JC, Scheffer IE, Petrou S, Dibbens LM, Berkovic SF et al. (2005) SCN1Amutationsandepilepsy. Hum Mutat. 25: 535–542.

Nava C, Lamari F, Héron D, Mignot C, Rastetter A et al. (2012) Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl Psychiatry 2:e179.

Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE et al. (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242-245.

O'Roak BJ1, Vives L, Fu W, Egertson JD, Stanaway IB et al. (2012a) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619-1622.

O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N et al. (2012b) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246-250.

Penagarikano O, Abrahams BS, Herman,EI, Winden KD, Gdalyahu A et al. (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.

Cell 147: 235–246.

Plummer JT, Evgrafov OV, Bergman MY, Friez M, Haiman CA, et al, (2013) Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. Transl Psychiatry 3:e316.

Prasad A, Merico D, Thiruvahindrapuram B, Wei J, Lionel AC et al. (2012) A discovery resource of rare copy number variations in individuals with autism spectrum disorder. G3 (Bethesda) 2(12):1665-1685.

Roohi,J, Montagna C, Tegay DH, Palmer LE, Devincent C et al. (2009) Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet. 46: 176–182.

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ et al. (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237-241.

Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D et al. (2012) SHANK1 Deletions in Males with Autism Spectrum Disorder. Am J Hum Genet 90(5):879-887.

Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C et al. (2007) Strong association of de novo copy number mutations with autism. Science 316:445-449.

Serajee FJ, Zhong H, Mahbubul Huq AH. (2006) Association of Reelin gene polymorphisms with autism. Genomics 87(1): 75-83.

Skuse DH, Lori A, Cubells JF, Lee I, Conneely KN et al. (2014) Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proc Natl Acad Sci U S A.111(5):1987-1992.

Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X et al. (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 318:71-76.

Thanseem I1, Nakamura K, Miyachi T, Toyota T, Yamada S et al (2010) Further evidence for the role of MET in autism susceptibility. Neurosci Res.68(2):137-141.

Uchino S, Waga C (2013) SHANK3 as an autism spectrum disorder-associated gene. Brain Dev. 35(2):106-110.

Vaags AK, Lionel AC, Sato D, Goodenberger M, Stein QP et al. (2012) Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet. 90(1):133-141

Veltman JA, Brunner HG. (2012) De novo mutations in human genetic disease. Nat Rev Genet. 13(8):565-575.

Wermter AK, Kamp-Becker I, Hesse P, Schulte-Körne G, Strauch K, Remschmidt H. (2010) Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. Am J Med Genet B Neuropsychiatr Genet. 153B(2):629-639.

Xiong Q1, Oviedo HV, Trotman LC, Zador AM.(2012) PTEN regulation of local and long-range connections in mouse auditory cortex. J Neurosci. 32(5):1643-1652.

Yan J, Oliveira G, Coutinho A, Yang C, Feng J et al. (2005) Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 10(4):329-332.

Yang SY, Cho SC, Yoo HJ, Cho IH, Park M et al. (2010) Association study between single nucleotide polymorphisms in promoter region of AVPR1A and Korean autism spectrum disorders. Neurosci Lett. 479(3):197-200.

Yirmiya N, Rosenberg C, Levi S, Salomon S, Shulman C et al. (2006) Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills. Mol Psychiatry 11(5):488-494.

Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K et al. (2013) Using whole-exome sequencing to identify inherited causes of autism. Neuron 77(2):259-273.