Autism spectrum disorders (ASDs), also known as pervasive developmental disorders (PDD), are a behaviorally defined group of neurodevelopmental disorders that are usually diagnosed in early childhood. They are characterized by varying degrees of restrictions in communication and social interaction and by atypical, repetitive behaviors. The phenotype of ASDs is extremely heterogeneous with differences from person to person in a wide range of symptoms and severity as well as differences between the various subtypes of ASDs (e.g., autistic disorder, Asperger, PDD [NOS]).
Multiple lines of epidemiologic evidence support the strong role of genetics in the etiology of ASDs.1–3
Results of population studies of unselected cases of autism are consistent with multifactorial inheritance. The reported recurrence risk for full siblings is 4% if the affected child is a girl and 7% if the affected child is a boy. Overall, 2–3% of families have more than one affected child (potentially because of a decreased occurrence of subsequent pregnancies). If a second child has autism, the recurrence risk is on the order of 25–35%. The calculated relative recurrence risks are 22.3 for autism and 13.4 for Asperger syndrome. The sibling risk ratio (λs
) is estimated to be 100–150. The calculated heritability (the proportion of phenotypic variance explained by the genotype) is around 90%. There is an excess of twins reported in affected sib pairs. Population studies show a concordance of 70% in monozygotic twins; 90% if the broader phenotypic definition is used. This is in contrast to a 3% concordance in dizygotic twins.2–5
As a group, ASDs occur three to four times more commonly in men. Such a sexual dimorphism suggests that X-linked genes play a major role in the etiology of the spectrum. However, whole genome screens have found only four minor linkages to the X chromosome, and X chromosome genes seem to account for a only a small portion of the overall genetic contribution. Evidence of linkage has been found to most autosomes, suggesting marked genetic heterogeneity. The most consistently reported linkages have been with chromosomal locations 15q11–13, 7q 22–31 (two loci with parent of origin effect), 13q, 17q 11 (male-specific locus), 2q, and 16p.6–11
Over the past decade, the reported incidence of ASDs has increased markedly with some estimates suggesting a quadrupling in 10 years. The current estimates for autism are now reported to be on the order of 10–60 per 10,000 individuals, if all forms of ASDs are considered. In fact, the Center for Disease Control and Prevention has recently estimated the prevalence of ASDs in the United States at approximately 5.6 per 1000 (1 of 155 to 1 of 160) children.12,13
This rise in the reported prevalence of ASDs is unlikely to represent a true “epidemic ” of the condition as has been suggested by some. Rather, it seems that, this reported increase can be attributed to better knowledge of the disease and its variability, broader diagnostic criteria, improved public and professional awareness, and a higher level of acceptance of the diagnosis.
The role of the clinical geneticist is to determine the etiology of the ASDs, if possible, and to provide counseling for the family. In recent years, there has been an explosion of new diagnostic options and tools available to the clinician. Several recent publications have also reported a host of “expanded phenotypes” for genetic and metabolic conditions in association with ASDs phenotypes.14–19
These factors have led to an increase in the number of referrals to the clinical geneticist and an increase in the diagnostic yield. Now, more than ever, medical genetics services are available to help families answer the question “Why?”
In deciding upon an evaluation plan, the clinical geneticist has the difficult task of balancing an ever-expanding list of available tests and possible diagnoses with the issues of cost, practicality, and expected yield. The guidelines put forth here outline a strategy of a tiered evaluation of the etiology of autism. These recommendations use evidence-based conclusions from the current available literature and cumulative clinical experience.