The results of this study of recurrence are notable in several respects and provide new information on the genetic epidemiology of autism spectrum conditions. First, there exists an aggregation of quantitative
autistic traits among unaffected children in multiple-incidence ASD families—most pronounced in males, but an absence
of such traits in single-incidence families, as initially observed in a prior study that included teacher-report data involving a smaller number of single-incidence families (7
). The absence of such aggregation in single-incidence families is also consistent with our recent taxometic analysis of the entire IAN data set (a predominantly single-incidence sample), indentifying categorical discontinuity (ASD vs. non-ASD) rather than graded levels of symptoms within a predominantly single-incidence family sample (6
). Second, we observed minimal effects of proband gender and level of functioning on the rate of sibling recurrence, but when using standardized quantitative criteria for designation of affected status, many more females are identified, and the gender ratio narrows to 3:2. Third, across all family types, and highly consistent with prior family studies, some 20% of presumed-unaffected siblings carry an historic diagnosis of language delay, over half of whom exhibited distinctly autistic speech. This may constitute a form of recurrence in a substantial minority of autism-affected families. Finally, the rate of sibling recurrence of categorically-defined
ASD in this sample is in keeping with prior estimates, though distinctly lower than that reported for nonidentical twins from the same registry (31% concordance rate reported by Rosenberg et al., 2009) (30
); whether this difference is explainable on the basis of a) factors that might raise recurrence risk in twins versus b) ascertainment bias favoring the enrollment of concordant over discordant twin pairs in this volunteer register will be a critical issue to resolve via future research in independent samples.
In summary we observed a range of manifestations of sibling recurrence in autism, to include: 1) categorically-defined ASD; 2) history of language delay with autistic speech qualities; and 3) the aggregation of quantitative (sub clinical) autistic traits. This third manifestation appears to be absent in single-incidence autism families. These disparate manifestations of recurrence may reflect differential mechanisms of genetic transmission of autism in the population, including (respectively): 1) rare recessive or de novo mutations (including chromosomal rearrangements) of substantial effect, which, in some cases, have accounted for sporadic cases of autism; 2) inherited mutations that may be variably expressed and result in varying degrees of social and language impairment (i.e. categorically-defined ASD, history of language delay with autistic speech) and/or sub clinical autistic impairment; and 3) common susceptibility alleles or rare variants of minor effect, which may operate in additive or epistatic fashion. We note that even among single-incidence families in which affectation status appears categorical, the distribution of quantitative trait scores for affected children extends well into the range of the distribution for the general population. Thus the continuum observed for autistic symptoms in nature may be composed of highly overlapping “segments”, each with its own mechanism (or mechanisms) of genetic transmission. Finally, the observation of a narrowing of the gender ratio when standardized quantitative criteria for affectation status are applied suggests the possibility that affected females may be under-ascertained when using traditional categorical methods for diagnostic assignment.
Limitations of the study are that the sample was not fully epidemiologic (rather a large volunteer register), not fully representative of the ethnicity of the population of U.S. children affected by ASD, and that the data were provided exclusively by parents, which potentially introduce a variety of biases including rater contrast effects. Higher levels of rater contrast are expected in parent-report data in clinically-ascertained families (a reason for the use of teacher-report data in our previous study (7
)) and may have actually resulted in underestimation
of the magnitude of familial aggregation among multiple-incidence families in this report. We note also that we were unable to directly compare the proportion of children with language delay in this sample with a population-based sample in which the same ascertainment methods were employed.
Several aspects of the data validate the reports of parents in this study, however, including the very high rate of reported diagnostic confirmation (98%) in families whose children underwent standardized testing for ASD (18
), the fact that parents’ report of a diagnosis corresponded closely with quantitative characterizations of social deficiency in their children (with nadirs closely corresponding to established “cutoffs” for clinical-level symptomatology), and that these results replicate what was observed by both teacher-report
data (minimizing the likelihood of rater contrast) and parent-report data in a smaller independent sample (7
). It is important to note that elevations in quantitative autistic traits ascertained by the SRS and Social Communication Questionnaire have been observed in samples of children seriously affected by other primary psychiatric conditions not ascertained in the IAN data collection (31
). Future research will need to explore the extent to which the quantitative distribution of autistic traits in these populations represent distinct or overlapping continua with those that characterize ASD.
On the basis of these findings, we propose careful reconsideration of what constitutes “recurrence”, informed by an understanding of the range of symptoms that aggregate in the siblings of ASD-affected probands (including females or twins) (30
), and that may more closely correspond to the manner in which autistic syndromes are intergenerationally transmitted. Among families of ASD subjects in this sample, fully 21.7% exhibited a recurrence of either ASD or history of language delay with autistic speech, with a broad distribution of sub clinical autistic traits among unaffected males in multiple incidence families.
Studies examining the association between autistic phenotypes and their underlying genetic (33
) or neurobiologic (34
) determinants may be optimized by including information about recurrence of the autistic syndrome and the aggregation of relevant subclinical phenotypes among first-degree relatives. The data from the current study provide new perspectives on the relative proportions of autism cases in the general population that manifest distinct patterns of familial aggregation, and should alert clinicians to the presence of both clinical and sub clinical ASD-related-syndromes that occur in the siblings of children affected by autism.