May 2014

Developing an Autism Guidebook for Medical Genetics

Sun, 18 May 14 14:20

Ten years ago, Irish researchers joined a major international research initiative aimed at delineating the genetic basis of autism spectrum disorders with a view to ensuring earlier diagnosis and individualised treatment of autism.  The collaboration involved researchers from 50 academic research institutions across North America and Europe who pooled their genomic technologies and expertise in a coordinated effort. 

The project was part funded by the Health Research Board and involved scientists and clinicians from TCD and UCD with Dr Sean Ennis’ group leading the UCD participation. It has generated over 300 peer reviewed articles including papers in Nature, Nature Genetics and Human Molecular Genetics.  The collaboration has recently published in the American Journal of Human Genetics what some consider will be the landmark paper from this initiative, Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders (link).

This research further enhances our understanding of the genetic basis for ASD revealing considerable etiological heterogeneity.  It has highlighted copy number variants (CNV) as an important risk factor in autism development, demonstrated the large number of genome-wide ASD-associated genes which are impacted by CNV and helps explain the sex bias of ASD.  The research highlights autism subtypes with increased risk of other complications and is considered a useful ‘guidebook’ for medical geneticists in the care of individuals with ASD.

Copy Number Variants (CNVs) are genetic changes involving the deletion or duplication of large segments of DNA that can impact multiple genes.  While standard genetic tests look for mistakes in individual genes, these often don’t reveal the existence of CNVs.  This research involved CNV testing of 2,446 families affected by autism comparing them with 4,768 individuals unaffected by neurologic or psychiatric disorders. 

CNVs were significantly more common among those affected by ASD.  The analysis reveals very large etiological heterogeneity with 36 different genetic loci found among 82 individuals with pathogenic CNVs.  The data also supports the hypothesis that a larger burden of CNVs is required among females before ASD is expressed, explaining why autism is more prevalent among males.  Many of the identified genes converge within interconnected functional groups which may provide possible diagnostic or therapeutic targets.  Affected genes are involved in cellular pathways associated with brain development, synapse function and chromatin regulation. Some affected genes are associated with elevated risks of other complications (e.g. seizures, muscular dystrophy, heart defects). 

Based on this work, researchers with the Autism Genome Project are calling for the wider use of copy number variants (CNVs) analysis as a step towards improved individualized diagnosis and treatment of autism.   The Irish Group, Dr Ennis and Dr. Regan from UCD and Professor Gallagher from TCD, are continuing to work on this interesting area of Autism Research by investigating CNVs at higher resolution on a subset of Irish patients, work that is supported by the National Children’s Research Centre and the Health Research Board.

About Autism

Autism is a general term used to describe a group of complex developmental brain disorders – autism spectrum disorders – caused by a combination of genes and environmental influences. These disorders are characterized, in varying degrees, by communication difficulties, social and behavioural challenges, as well as repetitive behaviours.   ASD ranges from mild to severe levels of impairment with cognitive function among individuals above average to intellectual disability. ASD is often accompanied by seizures and other medical problems.  An estimated 1 in 100 children in Ireland are on the autism spectrum.