The current study is the largest prospective investigation of ASD sibling recurrence yet conducted. The primary finding was a substantially higher rate of ASD in infant siblings of children with ASD than previously documented. Earlier investigations reported recurrence estimates ranging from 3% to 14%,6–8,10–12,14
whereas in this study, 18.7% of infants with at least 1 older sibling with ASD developed the disorder. The 2 strongest predictors of an ASD diagnosis were the gender of the infant and the number of affected older siblings. Male gender and multiplex family status were independent and significant predictors of an ASD outcome, with a 2.8-fold increase in the risk for ASD for male infants (25.9% of high-risk male infants versus 9.6% of high-risk female infants) and an additional twofold increase in risk if there was more than 1 older affected sibling (13.5% of simplex versus 32.2% of multiplex). The increased risk for male infants replicates previous research.10,11
The recurrence rate for multiplex families reported here (32.2%) is similar to that found in an earlier population-based study conducted in Utah (35.3%).10
Previous investigations also suggested that the gender of the proband was associated with recurrence rates,10,14
with ASD outcomes more likely if the older affected child was female. The current data did not support such a threshold polygenic model of inheritance, in that similar rates of recurrence were found in families with male and female probands, as previously reported by others.13
Additional proband, demographic, and family factors, such as proband IQ and autism severity, infant race, ethnicity and birth order, and parental education and age, also did not predict outcome. There was variability across sites in ASD outcome rates, which may reflect geographic diversity, regional variation, and/or method differences. Site heterogeneity was accounted for as a random variable in all statistical models and did not interact with any predictors of outcome.
The design of the current investigation minimized many of the limitations of earlier research, such as stoppage, overreporting, and ascertainment bias.15,16
Stoppage, or the tendency of couples with an affected child to stop reproducing, leads to an underestimate of recurrence rate if uncorrected.9
Earlier studies of large unrestricted samples reported that between 4% and 10% of families had more than 1 affected child,6–8,11
whereas studies that restricted the sample to families with later-born siblings reported higher sibling recurrence rates of between 9% and 14%.10,11
Stoppage was addressed in the current investigation, by design, through studying only families with later-born siblings.
Overreporting is a second threat to the estimation of sibling recurrence risk. Because of limitations in time and resources, the affected status of children in previous studies often was determined by parent report or record review,11,13
which has been demonstrated to inflate recurrence rate estimates.15
The present study addressed overreporting biases through prospective data collection and diagnostic methods that combined structured, reliable assessment tools with expert clinical diagnosis. Diagnostic outcome was determined at 36 months, an age at which multiple studies have documented excellent diagnostic stability, with over 85% of children retaining a diagnosis several years later.20,21
Because outcome was determined before the age that milder forms of ASD, such as Asperger disorder, are accurately diagnosed,22
the true recurrence rate may in fact be higher than that reported here.
There are several types of ascertainment bias that may affect recurrence rate estimates, particularly in samples such as this one, which were not epidemiologically ascertained. Of primary interest for the present study is the overinclusion of families who have developmental concerns about their later-born infant. Overselection of infants with preexisting developmental delays was minimized in the present investigation by the early age at enrollment, with two-thirds of the sample recruited before the age of 6 months, when behavioral signs and parent concerns of ASD are rare.17,23–26
That there were no effects of age at enrollment on rates of ASD outcomes suggests that overselection was not a significant bias in the present study.
Comparing the current sample to population-based studies of children with ASD also is relevant to evaluating ascertainment bias. The gender ratios of both the probands and the infants with ASD outcomes in this study were similar to those reported in the general ASD population.27,28
If multiplex families were overrepresented in the current sample, this could elevate recurrence rates, but this was not the case. The current sample was 6% multiplex (before the birth of the infant), whereas other studies report multiplex rates of approximately 10%.10,11,14
Together, this information suggests that the recurrence rates provided by this study were not overly biased, despite the fact that the sample was not epidemiologically ascertained. However, the true rate of sibling recurrence in the general population of families affected by ASD will ideally be estimated in the future through large population-based studies.
These results have significant family-planning and genetic-counseling implications.29,30
At the present time, genetic counseling for ASD is constrained by the fact that currently cited risk estimates are largely on the basis of data from the 1980s and 1990s, when earlier, less inclusive versions of the Diagnostic and Statistical Manual of Mental Disorders
were in use. The updated information provided in this report will give families risk estimates that more accurately reflect recurrence as defined by current diagnostic practice (ie, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
). Many families actually believe that the risk to later-born siblings is higher than either the current investigation or previous studies suggest it to be.31,32
If families base reproductive decisions on perceived risk of recurrence, it is important that they receive updated information about these risks. Genetic counseling most often is provided for mendelian disorders and is a complex undertaking for disorders of multifactorial inheritance that are influenced by multiple unknown susceptibility genes and other factors. Therefore, it is critical that these data are provided to families in a sensitive manner, with extensive counseling that helps them evaluate risk as we understand it at this time.33
It is important to convey that recurrence estimates are on the basis of group averages, and, in most cases, it is not yet possible to counsel parents regarding individual levels of risk. A thorough genetic work-up is essential as part of the etiologic investigation for all individuals with ASD and may have important implications for risk counseling.34
DNA collection for genotyping the current high-risk sample is underway and may, in the future, yield critical information about genetic etiologies of ASD.
Finally, this study highlights the importance of routine surveillance and rapid referral for infant siblings of children with ASD. Given the higher-than-expected recurrence rates, particularly for male infants and multiplex families, it is critical that primary care professionals closely monitor the development of infants who have older siblings with ASD, screening them routinely at well-child visits using a tool appropriate for infants.35–38
The red flags identified should be followed by immediate referral for infant intervention rather than adopting a “wait-and-see” attitude because early specialized intervention is considered best practice for ASD39,40
and may represent the best hope for reducing symptoms and overall disability in high-risk infants who are developing ASD.41