Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

Abstract

Autism spectrum disorders (ASDs), also known as pervasive developmental disorders, are a behaviorally defined group of neurodevelopmental disorders that are usually diagnosed in early childhood. They are characterized by varying degrees of limitations in communication and social interaction and by atypical, repetitive behaviors with an onset before 3 years of age. The phenotype of ASDs is extremely heterogeneous, with differences from person to person in a wide range of symptoms and severity as well as differences between the various subtypes of ASDs (e.g., autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified).Multiple lines of epidemiologic evidence support the strong role of genetics in the etiology of ASDs. 1-3 Results of population studies of unselected cases of autism are most consistent with multifactorial inheritance. Until quite recently, the accepted recurrence risk for full siblings of a child with autism has been in the range of 3-10%. [4][5][6] Overall, only 2-3% of families have more than one affected child (possibly because of voluntary avoidance of pregnancy after a child is diagnosed). Most studies have reported a sex bias in the recurrence risk in keeping with the presumption of a "multifactorial" mode of inheritance (higher risk if the affected person is of the less commonly affected sex). As such, the reported risk is 7% of another affected child if the first affected child is female and 4% if the first affected child is male. 7 If multiple children (two or more) have autism, the recurrence risk is on the order of 33-50% for any future pregnancy. 7 Two recent studies 8,9 have reported even higher recurrence risks of 11 and 19% with single-sibling involvement. The first 8 was a retrospective self-enrolled/self-identified study using an interactive website. The diagnosis was confirmed, but the identification of second siblings may be a source of ascertainment bias. The second 9 was an international multisite prospective study in 664 families with a calculated 19% recurrence risk. Interestingly, the typically reported sex bias was not noted in one of these studies. 8 Both were single studies that bear replication.The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulted in an increase in the number of referrals to clinical geneticist for the evaluation of persons with autism spectrum disorders. The primary roles of the geneticist in this process are to define etiology when possible, to provide genetic counseling, and to contribute to case management. In deciding on the appropriate evaluation for a particular patient, the geneticist will consider a host of factors: (i) ensuring an accurate diagnosis of autism befor...

Can genetic research motivate parents to pursue genomic testing for children with autism spectrum disorder?

“…In addition to its prospective uses for those receiving the test, another outcome of undergoing CMA for neurodevelopmental disorders is this information's potential role in advancing autism research [4,5].…”

“…Albeit the etiologies of ASD are not yet clearly identified, a substantial body of evidence has indicated the strong genetic basis of ASDs [1,[3][4][5]. Several Chromosomal disorders such as Fragile X and Down's Syndrome have also been identified as comorbid for ASD [6].…”

“…Of these, 8-21% of autism-linked genetic disorders exist in the form of a varying degree of point mutations known as copy number variants (CNVs) [1,8]. Genes that are considered CNVs for ASD can affect multiple points across numerous portions of the genome [4,8]. The variety of distances and number of CNVs might be associated with the complex range of phenotypes appearing on the autism spectrum [1,3].…”

Provision of Genetic Services for Autism and its Impact on Spanish Families

“…Fragile X testing should also be considered in males, since this entity accounts for approximately 2% of unselected ASD cases. Overall, a clinical and genetic evaluation including CMA identifies an etiology in approximately 15-30% of individuals (Schaefer and Mendelsohn 2013;Shen et al 2010). Achieving an accurate genetic diagnosis is of great importance, since genetic counseling based on a specific recurrence risk, as well as reproductive options to minimize the risk on subsequent pregnancies, can be provided to families.…”

Predicting autism spectrum disorder using blood-based gene expression signatures and machine learning

“…[3][4][5] Rapid advances in clinical genetic testing technology have increased the diagnostic yield from about 10% a few years ago to about 30%. 6) However, because many of these genetic variants show incomplete penetrance and variable phenotypic expression, 7) the use of gene expression signature biomarkers may be informative and provide the best model for identifying ASD cases.…”