Genetics of Autism

Introduction

Autism Spectrum Disorders (ASDs) are a group of clinically heterogeneous conditions all characterized by fundamental impairments in reciprocal social communication. There is incontrovertible evidence for a genetic contribution, derived both from family and twin studies. However, the specific allelic architecture, or nature of the genetic variation underlying ASDs, remains a matter of some debate.

Until fairly recently, the majority of gene discovery efforts have focused on the contribution of polymorphisms that are common (greater than 5% allele frequency) in the population. However, there are also multiple lines of evidence illustrating the importance of rare variation for this spectrum of disorders.

This presentation addresses the fundamental properties of genetic variation, describe the logic underlying the common variant-common disease and the rare variant common disease hypotheses, discuss the importance of structural as well as sequence variation, highlight recent results, and describe the way in these findings have offered initial insights into molecular mechanisms underlying ASD and at the same time challenged the current diagnostic nosology in psychiatry.

Featured Reading

Featured reading for the Genetics of Autism class lecture comes from:

El-Fishawy P and State MW. The Genetics of Autism: Key issues, recent findings and clinical implications. Psychiatr Clin North Am. 2010 Mar;33(1):83-105.

A recent comprehensive review of the Autism literature that addresses both the common variant-common disease and rare variant-common disease hypotheses with regard to ASD.

Read the abstract online at PubMed.gov or read it in full at the Elsevier Article Locator.

Reading List

The following are the required readings for the class session on the Genetics of Autism as well as a brief annotation from Dr. State on the reading material and a link to find the reading online or to purchase the book online.

El-Fishawy P and State MW. The Genetics of Autism: Key issues, recent findings and clinical implications. Psychiatr Clin North Am. 2010 Mar;33(1):83-105.

A recent comprehensive review of the Autism literature that addresses both the common variant-common disease and rare variant-common disease hypotheses with regard to ASD

View the Abstract at the PubMed website.

Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science. Jul 23 2004;305(5683):525-528.

One of the first (along with Iafrate et al 2004) demonstrations of the presence of submicroscopic chromosomal variations in the human genome in apparently healthy individuals

Read the full article at Google Docs.

Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet. Sep 2004;36(9):949-951.

One of the first (along with Sebat et al 2004) demonstrations of the presence of submicroscopic chromosomal variations in the human genome in apparently healthy individuals

Read the full article at Google Docs.

Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med. Mar-Apr 2002;4(2):45-61.

A comprehensive evaluation of common variant candidate gene studies demonstrating widespread difficulties with regard to reproducibility.

View the Abstract at the PubMed website.

Schaefer GB, Lutz RE. Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders. Genet Med. Sep 2006;8(9):549-556.

A comprehensive assessment of the utility of genetic screening of patients presenting with ASD.

View the Abstract at the PubMed website.

Sebat J, Lakshmi B, Malhotra D et al. Strong association of de novo copy number mutations with autism. Science. 2007 Apr 20;316(5823):445-9.

The first demonstration of an excess of large de novo copy number variants present in sporadic cases of autism, compared to multiply affected families or unrelated controls.

View the Abstract at the PubMed website.

Wang K, Zhang H, Ma D et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459 2009 (7246):528-533.

The first report of a common polymorphism carrying risk for Autism Spectrum Disorders meeting accepted criteria for statistical significance when considering the genome as a whole.

Download the paper at the University of Pennsylvania's Institute for Translational Medicine and Therapeutics website.

Chapter 2 (What Causes Autism?), and Chapter 13 (Dealing with Regression) from "A Practical Guide to Autism".

Volkmar, Fred; Wiesner, Lisa. "A Practical Guide to Autism". John Wiley & Sons, Inc. New Jersey, 2009.

Find this book online at the Publisher's website.

Media and Other Resources

Faculty and Guest Bios

Bio Profile

Matthew State, MD, PhD

Education

PhD, Yale University School of Medicine, 2001

MD, Stanford University, 1991

Research Interests

Asperger Syndrome; Autistic Disorder; Child Development Disorders, Pervasive; Mental Disorders; Schizophrenia, Childhood; Tic Disorders; Tourette Syndrome

Clinical Interests

Obsessive-Compulsive Disorder

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