Genetics of autism

The genetic architecture of autism spectrum disorders (ASD) is highly heterogeneous and involves hundreds of loci, each accounting for only a small fraction of cases.

To date, a genetic etiology is identified in ~20% of the patients, including chromosomal rearrangements, monogenic disorders, and copy number variants (CNVs). All these abnormalities are rare or even unique; the majority are de novo or X-linked maternally inherited in males, but can also be inherited with incomplete penetrance or variable expressivity.

Our research focuses on the elucidation of the genetic basis of ASDs, particularly on the contribution of rare variants. During the past years, we have used detailed clinical evaluation, screening of known genetic disorders, targeted sequencing of candidate genes and whole-genome CNV analysis to identify pathogenic variants in near 20% of the subjects in our sample and discover novel genes involved in ASD. For selected candidate genes harboring potentially pathogenic mutations, we perform functional in vitro and in vivo studies to validate their implication in the disorder and to gain insights into the cellular and molecular basis of ASD and related neurodevelopmental disorders.

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Autism spectrum disorders (ASD) encompass a group of behaviorally defined developmental disabilities characterized by impairments in social communication and by restricted and stereotyped behaviors and interests. The genetic architecture of ASD is highly heterogeneous and involves hundreds of loci, each of them accounting for only a small fraction of cases. To date, a genetic etiology is identified in ~20% of the patients, including chromosomal rearrangements, monogenic disorders, and copy number variants (CNV). All these abnormalities are rare or even unique; the majority are de novo or X-linked maternally inherited in male probands, consistent with purifying selection against deleterious genetic variants of major effect. Pathogenic variants can also be inherited, and are usually associated with incomplete penetrance or variable expressivity. All the genes and loci involved in ASD are also involved in intellectual disability, indicating that these two neurodevelopmental disorders share common genetic bases. Similarly, many genes involved in epilepsy can also result in ASD. These observations indicate that these genes cause a continuum of neurodevelopmental disorders that manifest in different ways depending on other genetic, environmental or stochastic factors.

The aim of our research is the identification of genes involved in ASD and understanding the pathophysiological mechanisms involved. During the past years, we have used detailed clinical evaluation, screening of known genetic disorders and microdeletion/microduplication syndromes, targeted sequencing of candidate genes, and whole-genome CNV analysis, to identify the genetic etiology in near 20% of subjects in our sample, previously diagnosed with “idiopathic” ASD. Our work has contributed to dispel the view that autism is a single disease entity, as commonly assumed, by demonstrating that autism is a behavioral manifestation of highly diverse genetic and genomic disorders.

Highlights

Our research and that of our collaborators has identified several genes involved for the first time in ASD, such as neurexin NRXN1 (cell adhesion molecule involved in synaptogenesis, presynaptic partner of neuroligins, also implicated in ASD) (Szatmari et al., 2007), SHANK3 (synaptic scaffolding protein, implicated in the 22q13 deletion syndrome) (Durand et al., 2007), and SHANK2 (Pinto et al., 2010). Mutations in these genes highlight the crucial role of synapse formation and function in the development of autism and other neuropsychiatric conditions.

Our group is one of the founding members of the Autism Genome Project (AGP), an international consortium aiming to identify the genetic factors underlying autism through the study of near 3,000 families. The AGP performed the first genome-wide screening of CNVs in autism in over 1,000 multiply affected families (Szatmari et al., 2007) and published the largest high-resolution screenings of CNVs in ASD (Pinto et al., 2010; 2014), highlighting the important contribution of rare CNVs to autism and implicating several novel genes as well as many candidate genes. Taken together, our results suggest that rare variants affecting ASD risk collectively encompass hundreds of genes. Despite this heterogeneity, many genes converge in interconnected functional modules providing diagnostic and therapeutic targets.

For selected candidate genes identified through the analysis of rare CNVs we perform functional in vitro and in vivo studies to validate their implication in ASD and to gain insights into the cellular and molecular basis of ASD and related neurodevelopmental disorders.

Collaborations

  • Paris Autism Research International Study (PARIS). The PARIS study is an international collaboration initiated by Marion Leboyer in France and Christopher Gillberg in Sweden, to collect families with one or more children with an autism spectrum disorder in Europe and the USA. In France, children and adolescents are mainly recruited at the Hôpital Robert Debré, Paris (Dr. Richard Delorme); adult subjects are recruited at the Hôpital Henri Mondor-Albert Chenevier, Créteil (Prof. M. Leboyer).
  • Autism Genome Project (AGP). The AGP is an international consortium bringing together researchers from over 60 centers in the USA, Canada, and Europe with the aim of identifying the genetic factors underlying autism through large scale genome wide studies in >3,000 families with one or more affected children.
  • Dr Anne-Claude Tabet, Unité de Cytogénétique, Hôpital Robert Debré, Paris
  • Dr. Joseph Buxbaum, Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York