ReviewEtiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting
Research Highlights
► The genetic architecture of autism is like that of intellectual disability, with many genetic and genomic disorders involved, each accounting for a small fraction of cases. ► A review of the literature identified 103 disease genes and 44 genomic disorders reported in subjects with ASD or autistic behavior. ► These loci have all been implicated in intellectual disability, indicating shared molecular mechanisms.
Introduction
Autism is the most severe manifestation of a group of neurodevelopmental disabilities known as autism spectrum disorders (ASDs), which also include Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS). ASDs are characterized by impaired social interaction and communication and by restricted interests and repetitive behaviors. Over 70% of individuals with autism have intellectual disability (ID), while epilepsy occurs in ~ 25% (Baird et al., 2006, Tuchman and Rapin, 2002). ASDs are identified in about 1% of children (Baird et al., 2006) and are four times more common in males than in females. There is a strong genetic basis to ASDs, as indicated by the recurrence risk in families, twin studies, and the co-occurrence with chromosomal disorders and rare genetic syndromes. The genetic architecture of ASDs is highly heterogeneous (Abrahams and Geschwind, 2008). About 10%–20% of individuals with an ASD have an identified genetic etiology. Microscopically visible chromosomal alterations have been reported in ∼ 5% of cases; the most frequent abnormalities are 15q11–q13 duplications, and 2q37, 22q11.2 and 22q13.3 deletions. ASDs can also be due to mutations of single genes involved in autosomal dominant, autosomal recessive and X-linked disorders. The most common single gene mutation in ASDs is fragile X syndrome (FMR1), present in ∼ 2% of cases. Other monogenic disorders described in ASD include tuberous sclerosis (TSC1, TSC2), neurofibromatosis (NF1), Angelman syndrome (UBE3A), Rett syndrome (MECP2) and PTEN mutations in patients with macrocephaly and autism. Rare mutations have been identified in synaptic genes, including NLGN3, NLGN4X (Jamain et al., 2003), SHANK3 (Durand et al., 2007), and SHANK2 (Berkel et al., 2010). Recent whole-genome microarray studies have revealed submicroscopic deletions and duplications, called copy number variation (CNV), affecting many loci and including de novo events in 5%–10% of ASD cases (Christian et al., 2008, Glessner et al., 2009, Marshall et al., 2008, Pinto et al., 2010, Sebat et al., 2007, Szatmari et al., 2007).
The accumulating number of distinct, individually rare genetic causes in ASD suggests that the genetic architecture of autism resembles that of ID, with many genetic and genomic disorders involved, each accounting for a small fraction of cases. In fact, all the known genetic causes of ASDs are also causes of ID, indicating that these two neurodevelopmental disorders share common genetic bases. An illustrative example is that of the X-linked neuroligin 4 (NLGN4X) gene, encoding a synaptic cell-adhesion protein. The first NLGN4X mutation was reported in a family with two brothers affected with ASD, one with autism and ID and the other with Asperger syndrome and normal intelligence (Jamain et al., 2003). Subsequently, a truncating mutation in NLGN4X was identified in a multi-generational pedigree with 13 affected males having either non-syndromic ID (10 individuals), ID with ASD (2 individuals) or ASD without ID (1 individual) (Laumonnier et al., 2004). This indicates that exploring ID genes in individuals with ASD can greatly expand the number of genes playing a causal role and identify additional molecular pathways.
Like ASDs, ID is a common and highly heterogeneous neurodevelopmental disorder, affecting 2%–3% of the population. About 25%–50% of ID is believed to be caused by genetic defects, and the large number of X-linked forms account in part for the 30% higher prevalence of ID in males compared to females (for recent reviews, see Ropers, 2010 and Gecz et al., 2009). Like in ASD, chromosomal abnormalities detected with conventional karyotyping account for about 5% of cases of ID, while novel molecular karyotyping methods have a diagnostic yield of 10%–15%. Again like in ASD, fragile X syndrome is the most common monogenic cause of ID. At least 50 genes have been identified that are associated with syndromic, or clinically distinctive, X-linked ID, and over 40 genes have been found to be associated with non-syndromic X-linked ID (Fig. 1). In addition, numerous autosomal genes, both dominant and recessive, have been linked to non-syndromic and syndromic ID. The distinction between syndromic and non-syndromic ID is not precise, and several genes, initially identified in syndromic conditions, were later reported in subjects with non-syndromic forms (e.g., ARX, CASK, JARID1C, FGD1 and ATRX).
Here, we review the different genetic and genomic disorders in which ASDs have been described as one of the possible manifestations. The findings indicate that, in contrast to a persisting claim that we know very little about the etiology of autism, there are more than 100, already identified, recurrent genetic defects than can cause ASD. All the genes and chromosomal rearrangements identified are well-known causes of ID, either syndromic or non-syndromic. Several have been involved in epilepsy, with or without ID, suggesting that this is another neurodevelopmental disorder that shares genetic risk factors with ASD. It is also of interest to see that the genes implicated in ASD go beyond those involved in synaptic function and affect a wide range of cellular processes.
Section snippets
Results
Table 1 presents a list of 103 known disease genes that have been reported to be mutated, deleted, duplicated, or disrupted by a translocation breakpoint in individuals with ASD or autistic features. Table 2 shows 44 recurrent genomic disorders and chromosomal aneuploidies reported in subjects with ASD/autistic traits. Only recurrent rearrangements were included. Fifteen genes from Table 1 are responsible for the phenotypic characteristics of microdeletion/microduplication syndromes listed in
Discussion
Our exhaustive review of the current literature identified more than 100 loci for which there is evidence for a causal role in ASDs. The majority have not been explored in ASD. Sequencing would be required to identify many of these mutations but to date only very targeted sequencing approaches have been performed in ASD research. There is every reason to believe that with whole-exome and whole-genome sequencing approaches mutations in these genes will be identified in additional cases, and many
Conclusion
The data presented in this review makes it abundantly clear that autism represents the final common pathway for numerous genetic brain disorders. Many well-recognized “ID genes” (which in fact do not cause ID in all affected individuals) can also cause ASD, with or without ID. Similarly, several genes initially identified in epilepsy samples can also result in ASD and ID. These findings indicate that these genes cause a continuum of neurodevelopmental disorders that manifest in different ways
Experimental procedures
An extensive literature search was conducted looking for articles describing genetic disorders in patients with autism, ASD, pervasive developmental disorder, Asperger syndrome, PDD-NOS, or autistic/autistic-like traits/features/behavior, using PubMed and Google Scholar, a well as follow-up of references cited in the papers thus identified. The genetic disorders considered all can have neurological manifestations, most commonly ID and/or epilepsy.
For disorders for which the association with ASD
Acknowledgments
I am deeply grateful to Mary Coleman for stimulating discussions about the role of medical disorders in the etiology of autism. I also thank Joseph Buxbaum for helpful comments on this manuscript, and Marion Pilorge for help with the figure.
References (379)
- et al.
The diagnostic utility of a genetics evaluation in children with pervasive developmental disorders
Genet. Med.
(2006) - et al.
Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP)
Lancet
(2006) - et al.
Recurrent 10q22–q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities
Am. J. Hum. Genet.
(2007) - et al.
Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree
Mol. Genet. Metab.
(2002) - et al.
Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams–Beuren syndrome region
Genet. Med.
(2007) - et al.
Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals
Eur. J. Med. Genet.
(2009) - et al.
Danon disease: an unusual presentation of autism
Pediatr. Neurol.
(2008) - et al.
Identification of MeCP2 mutations in a series of females with autistic disorder
Pediatr. Neurol.
(2003) - et al.
Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder
Biol. Psychiatry
(2008) - et al.
Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation
Am. J. Hum. Genet.
(2007)