ADVANCES IN GENOMIC TESTING ENHANCE UNDERSTANDING OF ASD

ASD represents a wide range of complex neurodevelopmental disorders resulting from multiple etiological factors. Dr. Szekely presented the new Diagnostic and Statistical Manual of Mental Disorders (DSM-5) definition, which emphasizes that ASD is primarily characterized by deficits in social communication and interaction and restricted, repetitive patterns of behaviors, interests, or activities beginning in the early developmental period [American Psychiatric Association. ASD DSM-5. 2013]. ID is common among children with ASD, with severe ID in about 50%, mild to moderate ID in 35%, and normal intellectual ability in 25% of affected children [Fombonne E. J Clin Psychiatry 2005].

The increasing incidence of ASD has spurred research on the wide phenotypic variability and highly heterogeneous genetics of these disorders. ASD is highly heritable, as shown in classical twin studies demonstrating 70% to 90% concordance in monozygotic twins [Bailey A et al. Psychol Med 1995]. Other risk factors include male gender and advanced maternal or paternal age.

Large-scale genomic studies have yielded a wealth of data on ASD and ID. Novel genome-wide approaches (ie, high resolution arrays using single nucleotide polymorphism [SNP] and copy-number variations [CNV] markers) have identified significantly enriched rare CNVs, including CNVs harboring new susceptibility genes encoding neuronal cell adhesion molecules and ubiquitin pathways [Sanders SJ et al. Neuron 2011; Pinto D et al. Nature 2010; Glessner IT et al. Nature 2009]. Analysis of the protein-coding portion of the genome with whole exome sequencing (WES) has detected many de novo and inherited single nucleotide mutations and rare variants in ASD. Using these and other sequencing technologies, genetic mutations have been identified in ∼20% of ASD cases, but none of the mutations individually accounts for >1% of cases.

Several single-gene syndromes are associated with a high rate of patients with ASD symptoms, including Fragile X and Rett syndromes. Many of these disorders are also associated with clinical abnormalities, including dysmorphic features, microcephaly, macrocephaly, and seizures.

Increased numbers of rare CNVs have been found in individuals with ID, many of which overlap with those found in ASD, epilepsy, schizophrenia, attention deficit disorder, and language impairment, suggesting, at least in part, common abnormalities in early brain development. More than 100 X-linked gene mutations have been associated with single-gene disorders in ID.

Evaluation of individuals with ASD and ID using advanced genomic methods can provide a diagnosis and etiology for the disorder, helping to determine prognosis and guide medical care while avoiding unnecessary testing. Genomic testing allows early intervention, counseling, and family planning, providing empowerment and closure to the family. According to the American College of Medical Genetics and Genomics (ACMG), advances in technology have increased the diagnostic yield from 6% to 10% to in the 30% to 40% range [Schaefer GB et al. Genet Med 2013]. The ACMG Practice Guidelines for ASD evaluation are summarized in Table 1. A similar diagnostic strategy is emerging for evaluating ID of unknown etiology, starting with chromosomal microarray (CMA) for first-line genetic testing [Schaefer GB et al. ACMG 2013].

Projected diagnostic yields expected in genetic testing for ASD are shown in Table 2 [Schaefer GB et al. ACMG 2013].

The clinical goals of ASD and ID evaluation are to provide affected individuals with tools to achieve their best potential and to provide the best care for the families. Further research on the phenotypic characteristics and their underlying biological mechanisms is needed to develop therapies based on the key vulnerabilities of the pathological mechanisms.

TARGETING GENE CLUSTERS IN ASD AND ID

Developing potential treatments for ASD and ID is a challenge due to the difficulty in defining clinical phenotypes, severity of the disorders, and the presence of comorbid conditions that can affect the response to treatment, according to Dr. Bolduc. Although there is significant phenotypic and genetic overlap between the 2 disorders, ASD is characterized primarily by restricted behavior and deficits in social communication, while ID is characterized by deficits in intellectual and adaptive functions. In fact, 50% to 85% of ASD patients have ID and 40% of ID patients have ASD [Brereton AV et al. Autism Dev Disord 2006; Matson JL, Shoemaker M. Res Dev Disabil 2009]. Additionally, 20% of novel ASD genes identified with exome sequencing were Fragile X targets [Darnell JC et al. Cell 2011].

The overlapping nature of biological pathways in these disorders suggests that the genes could potentially be clustered into groups to be then targeted by similar drug therapy. Among other ways, ASD and ID genes can be grouped according to their biological function—control of gene expression; regulation of protein synthesis; structural modification of the synapse and neuron; and functional modification of the synapse and neuron. Table 3 lists the genes and proteins in each of these pathways that are associated with ASD, ID, and related disorders. A summary of therapies targeting these pathways is also included in the table.

Large-scale genetic studies have shown that ASD and ID may have overlapping phenotypic and genetic features. ASD and ID genes may express different phenotypes if they are expressed in different cortical regions [Parishak. Cell 2013; Willsey AJ et al. Cell 2013]. Clustering ASD and ID genes by function into networks helps in understanding the disorders and in developing treatments targeting these genes. Dr. Bolduc presented a list of multiple online resources that can help clinicians and researchers stay up-to-date on these genetic disorders and related clinical trials: clinical description, OMIM.org; gene function, geneontology.org; where to test, Genetests.org; and treatments, ClinicalTrials.gov.