| Abstract: | ![]()
Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions—phenotypically and genetically—although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.The set of conditions diagnosed as autism spectrum disorders (ASDs) vary enormously in their presentation (1). The most severely impaired individuals—often those with intellectual disabilities, limited speech, and severe behavioral problems—can require lifelong care. At the other end of the functional spectrum, people diagnosed with ASDs can be verbally fluent and academically gifted and can achieve independence in adulthood (2, 3). The broad range of cognitive and behavioral profiles seen in diagnosed ASDs has been long viewed as a challenge by the research community (4). Although it is well established that (i) the cognitive/behavioral profile of people diagnosed with ASDs varies widely and (ii) the set of genetic factors related to ASDs varies widely (5, 6), the degree to which phenotype can be used to predict patterns in disease architecture remains unclear.Recent insights into the genetic influences on ASDs offer an opportunity to investigate this question through the lens of de novo vs. familial effects. On average, ASDs run in families. The siblings of children with ASDs are 10–20 times more likely to receive a diagnosis of ASD themselves (7, 8); the parents of children with ASDs are more likely to manifest autistic features, as well as a variety of other neuropsychiatric conditions, such as schizophrenia and bipolar disorder (9, 10). These epidemiologic observations are consistent with analyses suggesting that ASDs are influenced by thousands of common genetic variants transmitted between generations. It has been estimated that common, genotyped SNPs account for 20–60% of variation in ASD risk, although the effect of any individual SNP is likely very small (11–13). Many of these influences are shared with other psychiatric disorders (12, 14), which at least in part explains the familial clustering of different types of behavior problems.However, statistics about ASD heritability reflect an average. For example, there are likely many affected families for whom sibling recurrence risk is less than 10–20%. The strongest evidence toward this claim comes from studies of rare, severely deleterious genetic events that are associated with ASDs (15–20). Events of this type, for example copy number variants and loss of function (LOF) mutations, are often de novo (not seen in an affected individual’s parents). Although cases of ASDs involving a de novo mutation could reflect a concert of spontaneous and inherited genetic events, de novo events of large effect may reduce the likelihood of seeing psychiatric problems in an affected individual’s family members. |
