Autism is regarded as a highly genetic disorder, although the genes involved have proved difficult to identify (see Essay by D.H. Geschwind, page 391 of this issue). A focus on the genetic nature of autism provides a unique opportunity to consider its pathophysiological mechanisms. Perhaps surprisingly, indistinguishable autistic disorders can clearly be caused by many different genetic changes, a phenomenon generally referred to as genetic heterogeneity. The first genes implicated in autism were associated with broader syndromes that included autistic symptoms rather than with pure or nonsyndromic autism (for which the child psychiatrist Leo Kanner is generally credited with providing the original description). For instance, prominent autistic symptoms accompany a genetic metabolic disorder called phenylketonuria (PKU) (Fombonne, 1999
). In addition, children with mutations in the genes associated with tuberous sclerosis (TSC1, TSC2
) or in the PTEN
tumor suppressor gene show prominent autistic symptoms, although these patients would not generally be diagnosed with autism because they show broader symptoms (such as tumors or benign malformations, called hamartomata, of many structures including brain, skin, and kidney). Deletions of chromosome 22q11 (the region normally associated with velo-cardiofacial syndrome) are seen in about 1% of autistic children but again are typically accompanied by other features as well (cleft palate, congenital heart disease). Inverted duplications of proximal chromosome 15q are also associated with autistic symptoms but often cause prominent mental retardation as well.
Important clues about the mechanisms underlying autism come from the monogenic disorders Rett’s syndrome and Fragile × syndrome (see Essay by Kelleher and Bear, page 401 of this issue). Rett’s syndrome, caused by mutations in the human MECP2
gene, which encodes the methyl-cytosine binding protein, occurs almost exclusively in girls (mutations in this X-linked gene are lethal to males). Affected girls show normal development for 1–2 years, followed by the appearance of stereotyped repetitive hand movements and a regression of neurological and social skills. Similarly, one of the best-known disorders associated with autistic symptoms is the Fragile × syndrome. Males with Fragile × syndrome typically have developmental delays (for example, delays in walking or language) and somatic dysmorphology (for example, large ears, a large head), and so Fragile × is generally not referred to as autism per se. Although there are many syndromic forms of autism, it is also important to stress that 40% to 60% of autistic children show some degree of mental retardation (Giacometti et al., 2007
), although measuring IQ in autism may pose challenges. Also, some pediatric neurology clinics report that ~30% of autistic patients suffer from seizures (Fombonne, 1999
As clinical genetic testing becomes more frequent, more autistic children will receive specific genetic diagnoses. The same genetic defects associated with broader syndromes are now recognized to cause a spectra of abnormalities, including those found in some higher-functioning children with autism. For instance, deletion of 22q11 (Vorstman et al., 2006
), Fragile × gene abnormalities, or milder MECP2
mutant alleles (Moretti and Zoghbi, 2006
) are occasionally seen in children without the typical broader syndromes associated with these conditions. Why similar genetic abnormalities cause a range of phenotypes is an enduring mystery and may reflect the involvement of other genetic or nongenetic factors.
One of the areas that has seen the most rapid recent progress in autism genetics has come with the realization that up to 7%–10% of children with autism have a variety of de novo chromosomal deletions and duplications (Sebat et al., 2007
;Marshall et al., 2008
; Kim et al., 2008
). These deletion syndromes typically cause a spectrum of phenotypes that includes autism. Some chromosome aberrations have been helpful in identifying specific genes mutated in autism, and some of these genes appear to have brain-specific functions. For instance, × chromosome deletions implicated the NLGN3
genes (Jamain et al., 2003
) encoding neuroligins 3 and 4, which are synaptic adhesion molecules. Subsequent studies identified an NLGN4
mutation inherited in a large family with many affected males showing mental retardation and/or autism (Laumonnier et al., 2004
). These findings suggest that NLGN3
gene mutations are causes, albeit rare, of autism, mental retardation, and potentially other neuropsychiatric syndromes. The SHANK3
gene, which encodes a cytoplasmic binding partner of the neuroligins, was also identified based on a chromosomal deletion (Durand et al., 2007
). Chromosome deletions (Kirov et al., 2007
; Moessner et al., 2007
) and translocations (Kim et al., 2008
) involving the NRXN1
neurexin gene, which encodes an extracellular binding ligand for neuroligins, have implicated this gene in autism as well. Rare changes in CNTNAP2
, encoding contactin associated protein-like 2 (a neurexin superfamily member), are associated with autism, and common alleles of CNTNAP2
may increase the risk of developing autism. Even these mutations, which can affect the neuronal synapse, tend not to be highly specific for “pure autism” but rather cause a broader mental retardation phenotype in some patients and pure autism in others.
Why do many mutations associated with autism occur de novo, meaning they are present in the child but not in the parents or earlier ancestors? This is actually not surprising. Autistic children rarely marry and have children, so that the condition is subject to “negative evolutionary selection,” with affected patients having decreased fertility. This negative selection means that for mutations to be observed in the population they must frequently occur as de novo mutations. Such negative evolutionary selection is common to mutations associated with other severe diseases, especially those of childhood, for example mental retardation, epilepsy, or congenital heart disease (Lupski, 2007
). A recent study focused on identifying autosomal recessive loci in pedigrees with autism and recent shared ancestry (Morrow et al., 2008
). Autosomal recessive mutations, like sporadic mutations, also frequently reduce reproductive fitness. In this study, consistent with the finding of copy number variations (CNVs) in autism, multiple heterogeneous loci were implicated, but these loci represent potential inherited causes. Hence, by tracing shared ancestry this approach may provide an important way to identify inherited loci in heterogeneous neurodevelopmental conditions that reduce reproductive fitness.
Is it unusual that mutant forms of many different genes cause an overlapping or indistinguishable autistic phenotype? On the contrary, it appears to be the rule, at least for neurological disorders of the cerebral cortex, such as dementia, mental retardation, or epilepsy. Disorders that affect the cerebral cortex and its associated forebrain neural systems may uniquely define this genetic heterogeneity, perhaps because the forebrain requires many genes (likely >10,000) for normal development and function, yet the plasticity of forebrain structures appears tailor-made to redistribute and remap critical functions in response to perturbation. Hence, the cerebral cortex may provide essentially a “plastic reserve” to ameliorate genetic defects, which in turn results in there being a small number of stable, recognizable, abnormal states that multiple mutant genes converge upon.