Quantitative trait variation in ASD probands and toddler sibling outcomes at 24 months

Abstract

Background: Younger siblings of children with autism spectrum disorder (ASD) are at increased likelihood of receiving an ASD diagnosis and exhibiting other developmental concerns. It is unknown how quantitative variation in ASD traits and broader developmental domains in older siblings with ASD (probands) may inform outcomes in their younger siblings.

Methods: Participants included 385 pairs of toddler siblings and probands from the Infant Brain Imaging Study. ASD probands (mean age 5.5 years, range 1.7 to 15.5 years) were phenotyped using the Autism Diagnostic Interview-Revised (ADI-R), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Siblings were assessed using the ADI-R, VABS-II, Mullen Scales of Early Learning (MSEL), and Autism Diagnostic Observation Schedule (ADOS) and received a clinical best estimate diagnosis at 24 months using DSM-IV-TR criteria (n = 89 concordant for ASD; n = 296 discordant). We addressed two aims: (1) to determine whether proband characteristics are predictive of recurrence in siblings and (2) to assess associations between proband traits and sibling dimensional outcomes at 24 months.

Results: Regarding recurrence risk, proband SCQ scores were found to significantly predict sibling 24-month diagnostic outcome (OR for a 1-point increase in SCQ = 1.06; 95% CI = 1.01, 1.12). Regarding quantitative trait associations, we found no significant correlations in ASD traits among proband-sibling pairs. However, quantitative variation in proband adaptive behavior, communication, and expressive and receptive language was significantly associated with sibling outcomes in the same domains; proband scores explained 9-18% of the variation in cognition and behavior in siblings with ASD. Receptive language was particularly strongly associated in concordant pairs (ICC = 0.50, p < 0.001).

Conclusions: Proband ASD symptomology, indexed by the SCQ, is a predictor of familial ASD recurrence risk. While quantitative variation in social communication and restricted and repetitive behavior were not associated among sibling pairs, standardized ratings of proband language and communication explained significant variation in the same domains in the sibling at 24 months, especially among toddlers with an ASD diagnosis. These data suggest that proband characteristics can alert clinicians to areas of developmental concern for young children with familial risk for ASD.

Keywords: Autism; Communication; Development; Family study; Infant sibling; Language.

Fig. 1

Proband and sibling VABS-II composite score distributions. Histograms display a wide distribution of VABS-II adaptive behavior, communication, socialization, and motor composite scores for ASD probands and toddler siblings with and without ASD. Score distributions overlap for probands and toddler siblings, with younger siblings exhibiting generally better performance in all domains. Statistics comparing proband and sibling performance among pairs concordant for ASD are reported in Additional file 1: Table S3 in the online supplemental material

Fig. 2

Raw scatterplots and bivariate Pearson correlations among proband and sibling scores. Plots are shown for all VABS-II and MSEL scores found to be significantly associated among proband-sibling pairs in regression analyses. The left panel depicts proband-sibling associations between identical domains on the VABS-II (a, c, e), while the right panel depicts associations between proband scores on the VABS-II and sibling scores on related domains from the MSEL (b, d, f). Overall linear associations for the entire sample (all probands, all siblings) are depicted by black dashed regression lines with shaded gray confidence intervals; corresponding correlations (computed for ease of effect size interpretation) are denoted by gray boxes. Linear associations and Pearson correlations for concordant pairs (red) and discordant pairs (blue) are also shown. Significance levels are denoted as follows: ns, non-significant; *p < 0.05, **p < 0.01, ***p < 0.001. Generally stronger associations are found for concordant pairs in all domains, with individuals with ASD exhibiting a downward shift in score profiles for adaptive behavior and cognition. Highly similar patterns of proband-sibling associations are found for overall functioning (a, b), receptive language (c, d), and expressive language (e, f) using both parent-reported VABS-II measures and MSEL examiner-based assessments of sibling abilities at 24 months