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Unified genetic model for sporadic and inherited autism
Writing in a recent issue of PNAS, researchers have proposed a single genetic model to explain both sporadic and inherited forms of autistic spectrum disorder [Zhao X et al. (2007) PNAS 104(31):12831-12836].
Autism spectrum disorder (ASD) is a collection of developmental disorders, including autism and Asperger syndrome, characterized by varying degrees of impairment in communication skills and social interactions as well as restricted or repetitive patterns of behaviour. The incidence of ASD is nearly 1 in 150 children, affecting four times as many boys as girls. Although environmental effects cannot be ruled out, twin studies indicate that ASD has a strong genetic component despite being a complex, multifactorial disease. Monozygotic twins have a 60-92% concordance rate for ASD (depending upon the exact diagnostic criteria) whilst dizygotic twins show only 10% concordance [Bailey A et al. (1995) Psychol Med 25(1):63-77].
Affected families are generally divided into those containing just one autistic child (‘simplex’), which is often a sporadic case, and those with multiple autistic siblings (‘multiplex’) where ASD appears to be inherited. By analysing data from the Autism Genetic Resource Exchange (AGRE) consortium and the Interactive Autism Network (IAN), lead researcher Michael Wigler and his co-workers have proposed an overarching genetic theory to explain both sporadic and inherited ASD. Specifically, that autism is caused by de novo germline mutations, which could strike at any number of critical genetic loci, in anyone, at any time. Consistent with the “extreme male brain” theory of autism, females are more resistant to these mutations than males resulting in a significantly higher penetrance in males. According to this unified theory, sporadic ASD in low-risk families is due to spontaneous mutations in the parental germ cells, with high penetrance in males and low penetrance in females. Inherited ASD results from resistant, largely unaffected individuals (predominantly female carriers) passing these mutations on to their offspring in a dominant fashion.
Comment: This theory neatly explains the twin data and the pattern of inheritance of ASD in males. The hypothesis also makes a number of strong predictions, most notably that there should be higher incidence of ASD with advancing parental age as the number of germline mutations increases. Intriguingly, the results from a number of studies looking for just such a correlation with both paternal and maternal age are wholly inconsistent. This work also has wide reaching implications, not only for ASD, but more broadly, for our understanding of genetics. Germline mutations may play a greater role in disease than previously recognized and, given the frequency and complexity of ASD, the rate of de novo mutations in humans per generation may turn out to be surprisingly high.
Keywords: Disease Susceptibility (Genetic)