1. Home
  2. MOJCSR
  3. MOJCSR 04 00085
Submit manuscript...
MOJ
eISSN: 2374-6912

Cell Science & Report

Mini Review Volume 4 Issue 2

Genetic basis of autism spectrum disorder 

Nadeem Kizilbash,1 Tanveer Ahmad Khan,2 Shumaila Samad Khan,3 Faiza Meer4

1Department of Medical Laboratory Technology, Northern Border University, Saudi Arabia
2Faculty of Pharmacy, Al-Jouf University, Saudi Arabia
3Department of Biotechnology, University of Karachi, Pakistan
4Faculty of Allied Health Sciences, The University of Lahore, Pakistan

Correspondence: Department of Medical Laboratory Technology, Northern Border University, Saudi Arabia

Received: April 18, 2017 | Published: May 4, 2017

Citation: Kizilbash N, Khan TA, Khan SS, et al. Genetic basis of autism spectrum disorder. MOJ Cell Sci Rep. 2017;4(2):62-64. DOI: 10.15406/mojcsr.2017.04.00085

Download PDF

Abstract

Autism Spectrum Disorder (ASD) comprises a wide range of neuro-developmental disorders characterized by difficulties with social communication and interaction, as well as restricted and repetitive patterns of behavior, interests and activities. It has a number of symptoms including cognitive, behavioral, and sensory symptoms. In addition, sleeping and eating difficulties, synesthesia as well as dysregulation and difficulty with initiation, planning and organization of tasks, are present. The identification of chromosomal abnormalities and Mendelian syndromes among individuals with Autism, along with linkage data from genome screens and candidate-gene studies, has helped delineate the complicated genetics that underlies Autism Spectrum Disorder.

Keywords:genetic, autism spectrum disorder, genetic mutations, chromosomal microarrays

Literature survey

The greatest progress in the discovery of genetic causes of Autism is from identification of genetic mutations and disorders that can predispose to Autism. Using standard evaluation techniques such as the use of chromosomal microarrays (CMAs), a genetic cause can be identified in 20-25% of children in the Autism spectrum. A small number of cases have been discovered by tracing exposure to specific teratogens.1 For the remaining 75-80% of the cases, the causes remain unknown. Medical Genetics clinics have found the highest percentage of disorders, whereas specialized Autism clinics have found the lowest.2,3 The Genetic Association Database4 provides online access to genetic data for Autism and other disorders. Many reviews of the current status of candidate genes and loci are available.5–14 SFARIGENE is a new web-based search engine for candidate genes associated with ASD.14 Table 1 lists some of the known Autism-related genes organized by pathogenesis of the disease. Particularly interesting are the synaptic cell adhesion molecules such as Neurexin 1, Neuroligin 3 and 4, and SHANK3, which implicate Glutaminergic synapse abnormalities with ASD. Mutations in the X-linked Neuroligin-3 (NLGN3) and Neuroligin-4 (NLGN4X and NLGN4Y) genes6,15 have been linked to Autism.16,17 Laumonnier et al.17 have identified a two base-pair deletion in NLGN4 in members of a French family exhibiting X-linked mental retardation. Jamain et al.16 identified a C-to-T transition in the NLGN3 gene in two siblings, one with autism and the other with Asperger Syndrome. People suffering from ASD and carrying mutations in NLGN4 and NLGN3 are typically non-dysmorphic. Genetic testing of NLGN4 and NLGN3 is important in families suspected of having X-linked Autism.17 The SHANK3 gene is crucial for the development of language and social cognition. SHANK3 mutations and small cytogenetic rearrangements have been implicated with ASD.18,19 In addition, SHANK3 mutations have been found in Attention Deficit Hyperactivity Disorder (ADHD) and language disorders; suggesting that they may cause disease by acting synergistically with other genes.

Chromosomal abnormalities at the 15q11-q13 locus are commonly found in people with Autism. A “chromosome 15 phenotype” has also been described in individuals with chromosome 15 duplications.20 Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA A receptor subunit and UBE3A genes on chromosome 15q11-q13 (Table 1). Mutations in the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with Autism than in non-Autistic populations. In addition, animal models and linkage data from genome screens have implicated the oxytocin receptor at 3p25-p26.21

Protein Name (Function)

Gene/Locus

Neuronal Cell Adhesion and/or Synapse Function

Neuroligin 3 (synapse formation and function)

NLGN3X Xq28

Neuroligin 4 (synapse formation and function)

NLGN4X Xp2323

Neurexin 1 (transsynaptic binding partner for Neuroligin)

NRNXN1 2p163

SH3 and multiple ankyrin repeat domains (organizes post synaptic density and binds Neuroligin)

SHANK3 22q13

Contactin-associated protein-like 2 (synaptic binding partner for contactin molecules involved in neuronal migration)

CNTNAP2 7q36

Contactin 4 and Contactin 3 (neuronal expressed adhesion molecules)

CNTN4 and CNTN3
6p26-p25

Protocadherin 10 (cadherin-related neuronal receptor)

PCDH10 4q28

Neuronal cell adhesion molecule

NRCAM 7q31

Neuronal Activity Regulation

Methyl CpG-binding protein 1 (CAN methylation-dependent transcriptional repressor)

MECP2 Xq28

Ubiquitin protein ligase E3A

UBE3A 15q11-q13

Deleted in Autism

DIA1 (c3orf58) 3q

Ataxin 2-binding protein 1

A2BP1 16p13

Neurodevelopmental Genes

Engrailed 2 (homeobox gene involved in midbrain and cerebellum development)

EN2 7q36

Homeobox A1 (involved in hindbrain development)

HOXA1 17p15.3

Homeobox B1 (involved in hindbrain development)

HOXB1 17q21-22

Reelin (signaling protein involved in neuron migration)

RELN 7q22

WENT2 (signaling protein involved in embryonic patterning, cell proliferation and cell determination)

WNT2 7q31

FOXP2 (transcription factor involved in embryogenesis and neural functioning)

FOXP2 7q31

ARX homeobox gene

ARX Xp22.13

Patched domain containing 1 gene

PTCHD1 Xp22.11

Sodium Channel

Sodium channel, voltage-gated, type VII

SCN7A 2q

Na+/H+ exchanger isoform 9

SLC9A9 (NHE9)
3q24

Calcium Channel

Calcium channel, voltage-dependent, type I, alpha 1C subunit

CACNA1C
12p13.3

Calcium channel, voltage-dependent, alpha 1H subunit

CACNA1H
16p13.3

Calcium channel, voltage-dependent, type I, alpha 1F subunit

CACNA1F
Xp11.23

Neurotransmitter Genes

GABA receptor Subunits

GABRB3, GABRA5, GABRG3
15q11.2-q12

Serotonin Receptor

SLC6A4
17q11.1-q12

Table Some of the known Autism-related genes

Future direction

Awareness of the symptoms and causes of Autism is relevant for a pediatrician. In light of the increasingly high prevalence of ASD, pediatricians are likely to come across cases of this disorder in their practices. However, the genetics of Autism is still far from understood since we are only beginning to understand what controls human behavior. Promising strategies need to be applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, can provide an insight into Autism Spectrum Disorder, in which both genetic and phenotypic heterogeneity is a dominant theme.

Acknowledgements

None.

Conflict of interest

The author declares no conflict of interest.

References

  1. Miles JH. Autism spectrum disorders––a genetics review. Genet Med. 2011;13(4):278–294.
  2. Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders:2013 guideline revisions. Genet Med. 2013;15(5):399–407.
  3. Miles JH, Takahashi TN, Bagby S, et al. Essential versus complex autism: definition of fundamental prognostic subtypes. Am J Med Genet A. 2005;135(2):171–180.
  4. Becker KG, Barnes KC, Bright TJ, et al. The genetic association database. Nat Genet. 2004;36(5):431–432.
  5. Freitag CM, Staal W, Klauck SM, et al. Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry. 2010;19(3):169–178.
  6. Buxbaum JD. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci. 2009;11(1):35–43.
  7. Sutcliffe JS. Insights into the pathogenesis of autism. Science. 2008;321(5886):208–209.
  8. Morrow EM, Yoo SY, Flavell SW, et al. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008;321(5886):218–223.
  9. Autism Genome Project Consortium, Szatmari P, Paterson AD, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39(3):319–328.
  10. Barbaro J, Dissanayake C. Autism spectrum disorders in infancy and toddlerhood: a review of the evidence on early signs, early identification tools, and early diagnosis. J Dev Behav Pediatr. 2009;30(5):447–459.
  11. Gupta AR, State MW. Recent advances in the genetics of autism. Biol Psychiatry. 2007;61(4):429–437.
  12. McKusick VA. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet. 2007;80(4):588–604.
  13. Banerjee Basu S, Packer A. SFARI Gene: an evolving database for the autism research community. Dis Model Mech. 2010;3(3–4):133–135.
  14. Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903–911.
  15. Wang K, Zhang H, Ma D, et al. Common genetic variants on 5p14. 1 associate with autism spectrum disorders. Nature. 2009;459(7246):528–533.
  16. Jamain S, Quach H, Betancur C, et al. Mutations of the X–linked genes encoding Neuroligin NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34(1):27–29.
  17. Laumonnier F, Bonnet–Brilhault F, Gomot M, et al. X–linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet. 2004;74(3):552–557.
  18. Durand CM, Betancur C, Boeckers TM, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39(1):25–27.
  19. Moessner R, Marshall CR, Sutcliffe JS, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81(6):1289–1297.
  20. Folstein SE, Rosen–Sheidley B. Genetics of austim: complex aetiology for a heterogeneous disorder. Nat Rev Genet. 2001;2(12):943–955.
  21. Wu S, Jia M, Ruan Y, et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry. 2005;58(1):74–77.
Creative Commons Attribution License

©2017 Kizilbash, et al. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.

Citations

Journal Menu

Useful Links