ReviewAutism genetics
Introduction
Since the first description of autism in 1943 by Leo Kanner, who defined “enclosure in one's self” as the distinctive trait shared by a cohort of eleven children [1], extraordinary advances have been achieved in understanding the physiopathology underlying this complex disorder. Autism, the prototypic pervasive developmental disorder (PDD), is characterized by onset prior to 3 years of age and by a triad of behavioral signs and symptoms, including (a) hampered verbal and non-verbal communication, (b) lack of reciprocal social interaction and responsiveness, and (c) restricted, stereotypical, and ritualized patterns of interests and behavior [2], [3]. Autism spectrum disorder (ASD) is a broader diagnostic category, encompassing autistic disorder as well as the less severe Asperger Disorder (AD) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). ASD will be the single diagnostic category adopted by DSM-V, although DSM-V criteria may not consistently detect AD and PDD-NOS as part of ASD [4]. Finally, the “broad autism phenotype” includes individuals with some signs and symptoms of autism, not meeting full criteria for ASD [5]. Collectively, these diagnostic categories and their change over time clearly speak to the difficulty in categorizing deficits in social cognition which are dimensional and quantitative in real life, rather than categorical [6].
ASD is characterized by striking clinical heterogeneity, seemingly underlied by an equally impressive degree of etiological heterogeneity. Researchers have so far aimed to address this great heterogeneity following two complementary strategies, the analysis of endophenotypes and genetic studies. Endophenotypes are familial and heritable quantitative traits associated with a complex disease and able to identify subgroups of patients possibly sharing homogeneous pathophysiological underpinnings [7]. The best established endophenotypes in autism research have been reviewed elsewhere [8]. On the other hand, autism has conclusively been recognized as the neuropsychiatric disorder with the greatest genetic component, due to monozygotic twin concordance rate as high as 73–95%, extraordinary heritability (>90%, as estimated by twin studies), and a noticeable sibling recurrence risk (5–6% for full-blown autistic disorder, approximately 15–25% for broad ASD) [9]. These heritability estimates, obtained mainly in the UK and in Northern Europe in the early 1990s, were recently confuted by a twin study undertaken on a California twin sample, compatible with a larger proportion of variance explained by shared environmental factors as opposed to genetic heritability (55% vs. 37% for strict autism, respectively) [10]. Conceivably, the relative weight of genetic and environmental factors may be region-specific and could be changing over time, as less severe forms of the disease are increasingly diagnosed within the spectrum. However, the related increase in sibling recurrence risk, estimated by recent baby sibling studies at 18.7% (26.2% for males and 9.1% for females) [11], and the presence of mild autistic traits in many first-degree relatives of patients with autism [5] still indicate a strong genetic component in ASD. Linkage and association studies have identified numerous susceptibility genes, located on various chromosomes, especially 2q, 7q, 15q and on the X chromosome. The clinical heterogeneity of ASD is thus believed to at least partly reflect the complexity of its genetic underpinnings, whose general underlying mechanisms include different modes of inheritance and gene–environment interactions. Here we will review the genetics of ASD moving from monogenic forms to the most recent contributions provided by genome-wide association and whole-exome sequencing studies.
Section snippets
Monogenic autisms
Autism can be part of a known genetic syndrome. This instance occurs in approximately 10% of all ASD cases, it is typically associated with malformations and/or dysmorphic features (“syndromic” autism) and, unlike “idiopathic” or “primary” ASD, it shows an equal male:female sex ratio [12], [13], [14].
Well-known genetic or genomic disorders can encompass autistic features in their clinical presentation, such as fragile X syndrome, tuberous sclerosis, neurofibromatosis, untreated phenylketonuria,
Non-syndromic autism: the role of common variants
In a complex disease like autism, it is conceivable that functional common polymorphisms can confer vulnerability or protection. Thus, according to Falconer's threshold model [141], a host of unfavourable common variants could even cause a disease phenotype, either directly, or by lowering the sensitivity threshold to the point of conferring pathogenicity to widespread environmental agents. This scenario is supported by several recent studies, demonstrating, for example, a moderate to high
Recent advances in the genetics of autism spectrum disorder: the impact of whole-exome sequencing
Traditional approaches for gene mapping from candidate gene studies to positional cloning strategies have been applied for Mendelian disorders. Since 2005, next-generation sequencing (NGS) technologies are improving as rapid, high-throughput and cost-effective approaches to fulfil medical sciences and research demands [163]. Whole-exome sequencing (WES) has recently been introduced to identify rare or novel genetic defects from genetic disorders. Particularly, ASD is a model disease to apply
Conclusions
The latest advances in the field of autism genetics highlight the striking complexity of its underlying pathophysiology. It is expected that high-throughput molecular screenings, such as high resolution array-CGH, whole-exome and whole-genome sequencing, as well as transcriptomic analysis, will further increase our understanding of the genetic underpinnings of ASD. Specific rare genetic variants have been convincingly shown to cause autism, at least in some cases. However, genotype–phenotype
Acknowledgments
The authors gratefully acknowledge all the patients and families who participated in our studies, and financial support by the Italian Ministry for University, Scientific Research and Technology (PRIN n.2006058195 and n.2008BACT54_002), the Italian Ministry of Health (RFPS-2007-5-640174 and RF-2011-02350537), the Fondazione Gaetano e Mafalda Luce (Milan, Italy), Autism Aid ONLUS (Naples, Italy), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), and the Innovative
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