Heterogeneity and Homogeneity Across the Autism Spectrum: The Role of Development

Abstract

Autism is a lifelong, highly prevalent, and strongly genetic disorder defined by impairments in social and communicative function and by pronounced behavioral rigidities. 1 Volkmar F Lord C Bailey A Schultz RT Klin A Autism and pervasive developmental disorders. J Child Psychol Psychiatry. 2004; 45: 135-170 Crossref PubMed Scopus (576) Google Scholar Despite common areas of impairment that define autism as a condition, individuals with autism show a vast clinical variability in the expression and severity of their symptoms. This heterogeneity spans the entire range of IQ and language function and a wide array of communicative, social, and behavioral disabilities. At the level of genetics, the variability seems comparable: although more and more susceptibility loci are being identified, each is thought to account for only a small number of overall cases (e.g., see reference 2 Weiss LA Shen Y Korn JM et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008; 358: 667-675 Crossref PubMed Scopus (1294) Google Scholar ). Likewise, de novo mutations may play a causal role in a relatively large percentage (∼10%) of individuals with autism who do not have an affected first-degree family relative. 3 Zhao X Leotta A Kustanovich V et al. A unified theory for sporadic and inherited autism. Proc Natl Acad Sci. 2007; 104: 12831-12836 Crossref PubMed Scopus (245) Google Scholar Pursuit of research focused on “simplex” and “multiplex” families (i.e., with only one or with more than one sibling affected) has led to insights on potential modes and risks of inheritance, necessitating a unified genetic theory for sporadic and inherited autism. 3 Zhao X Leotta A Kustanovich V et al. A unified theory for sporadic and inherited autism. Proc Natl Acad Sci. 2007; 104: 12831-12836 Crossref PubMed Scopus (245) Google Scholar However, none of these advances have yet successfully addressed the phenotypic variability of autism, such as range of severity among siblings, or the skewed sex distribution (many more male subjects than female subjects are affected); in fact, there is as yet little in the new findings that inform our understanding of the behavioral and cognitive aspects of the syndrome. One possibility is that “modifier” genes may have an impact on phenotypic expression, but these have not been identified yet. However, what is certain is that genotypic heterogeneity is one of the greatest obstacles to identification of discrete causes of autism, 1 Volkmar F Lord C Bailey A Schultz RT Klin A Autism and pervasive developmental disorders. J Child Psychol Psychiatry. 2004; 45: 135-170 Crossref PubMed Scopus (576) Google Scholar and it presents a formidable hurdle to developing effective treatments targeting the causes of the syndrome and not only its behavioral symptoms.