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The Molecular Basis of Autism pp 33–66Cite as

Genetics of Autism Spectrum Disorders: The Opportunity and Challenge in the Genetics Clinic

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Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

The involvement of genetic etiology in autism spectrum disorders (ASDs) was first suggested from a twin study reported in 1970s. This initial observation has then been validated in many subsequent studies. The identification of single genes in syndromic ASDs in 1990s provided the evidence to support a genetic cause of ASDs. Since 2005, genome-wide copy number variant and sequence analyses have uncovered a list of rare and highly penetrant copy number variants (CNVs) or single nucleotide variants (SNVs) associated with ASDs which strengthen the claim of a genetic etiology for ASDs. However, the cause in majority of ASDs (> 75 %) remains elusive. The increasing prevalence of ASD also has intensified a debate about the role of non-genetic factors, such as epigenetics, environment, and gene and environment interaction, in the ASD etiology. Although it remains a significant challenge to determine the cause in majority cases of ASDs, the findings from ASD genetics studies now support an important application for molecular diagnostics in the clinical genetics evaluation of ASDs. Various molecular diagnostic assays including single gene tests, targeted multiple gene panels and copy number analysis are all appropriate to be considered in the clinical genetics evaluation of ASDs in clinics. Whole exome sequencing could also be considered in selective clinical cases. However, the challenge remains to determine the causal role of the various types of genetic variants identified through molecular testing. The variable expressivity, pleiotropic effect and incomplete penetrance associated with CNVs and SNVs also present a significant challenge for genetic counseling and prenatal diagnosis.

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Abbreviations

ASD:

Autism spectrum disorder

AOH:

Absence of heterozygosity

CGH:

Comparative genomic hybridization

CMA:

Chromosomal microarray analysis

CNV:

Copy number variant

DSM:

Diagnostic and Statistical Manual of Mental Disorders

CRISPR:

Clustered Regularly Interspaced Short Palindromic Repeats

LOF:

Loss of function

MLPA:

Multiplex Ligation-dependent Probe Amplification

NGS:

Next generation sequencing

PMS:

Phelan-McDermid syndrome

TGP:

Targeted gene panel

VCFS:

Velocardiofacial syndrome

VUS:

Variant of unknown significance

WES:

Whole exome sequencing

WGS:

Whole genome sequencing

SNP:

Single nucleotide polymorphism

SNV:

Single nucleotide variant

FISH:

Fluorescence in situ hybridization

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Acknowledgement

Y.H.J is supported by National Institute of Health Grant MH-1089441, Autism Speaks, Ruth K. Broad Foundation and Prader-Willi syndrome research foundation. YW is supported by Nature Science Foundation of China (NSFC 81071116), Shanghai science and technology commission (12XD1401100), and China Ministry of Health special scientific research funds (201302002).

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Authors and Affiliations

  1. Department of Neurology, The Children’s Hospital of Fudan University, Shanghai, P. R. China

    Yi Wang M.D., Ph.D. & Xiu Xu M.D., Ph.D.

  2. Department of Pediatrics, Duke University School of Medicine, 27710, Durham, NC, USA

    Ping Wang Ph.D., Jennifer Goldstein Ph.D., C.G.C., Allyn McConkie Ph.D. & Yong-Hui Jiang M.D., Ph.D. (Advisory Professor)

  3. Department of Child Health Care, The Children’s Hospital of Fudan University, Shanghai, P. R. China

    Xiu Xu M.D., Ph.D. & Yong-Hui Jiang M.D., Ph.D. (Advisory Professor)

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Sau W. Cheung Ph.D., M.B.A.

  5. Departments of Pediatrics and Neurobiology, Duke University School of Medicine, 27710, Durham, NC, USA

    Yong-Hui Jiang M.D., Ph.D. (Advisory Professor)

  6. The Children’s Hospital of Fudan University, Shanghai, China

    Yong-Hui Jiang M.D., Ph.D. (Advisory Professor)

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  1. Yi Wang M.D., Ph.D.
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  6. Sau W. Cheung Ph.D., M.B.A.
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  7. Yong-Hui Jiang M.D., Ph.D.
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Correspondence to Yong-Hui Jiang M.D., Ph.D. .

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  1. Neuroscience and Pharmacology MMC 392, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    S. Hossein Fatemi

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Wang, Y. et al. (2015). Genetics of Autism Spectrum Disorders: The Opportunity and Challenge in the Genetics Clinic. In: Fatemi, S. (eds) The Molecular Basis of Autism. Contemporary Clinical Neuroscience. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2190-4_4

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