A Comparison of High-Risk Siblings with Multiplex and Simplex Familial Risk Status: A Baby Siblings Research Consortium Study

Background: Converging evidence suggests that there are multiple genetic pathways to autism spectrum disorder (ASD). One high-risk group that has been studied widely includes infants with older siblings with ASD, with risk modulated by the number of affected individuals in a family (multiple affected: multiplex, one affected: simplex). Investigation of multiplex siblings offers a unique opportunity to determine the quality of differences in early development associated with heightened genetic load for ASD in children with and without ASD outcomes. This study contrasts developmental profiles associated with different levels of familial risk in a large, multi-site sample of children from the Baby Siblings Research Consortium (BSRC) database.

Objectives: To compare children with multiplex and simplex familial risk for ASD on: (1) rates of ASD, atypical, and typical outcomes at 36 months; (2) developmental abilities, adaptive skills, and ASD symptoms within no ASD and ASD outcome groups.

Methods: Participants included 885 (simplex: 806, multiplex: 79) children with familial risk who were enrolled in longitudinal studies across 10 BSRC sites. Simplex children had one older sibling with ASD and multiplex children had two or more older siblings with ASD. Developmental abilities were measured with the Mullen Scales of Early Learning (MSEL), adaptive skills with the Vineland Adaptive Behavior Scales-2^nd Edition (VABS-II), and ASD symptoms with the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R). Children were placed into one of three groups at 36 months: Typical (MSEL ³85, ADOS <3), Atypical (MSEL <85, ADOS severity ³3), ASD (Clinical Best Estimate & ADOS ³4).

Results: See Table 1 for detailed results and statistical analyses. (1) Multiplex children were less likely than simplex children to be classified as Typical and more likely to be classified as ASD or Atypical. (2a) In the no ASD group, multiplex-no ASD children had lower MSEL scores than simplex-no ASD children; the Receptive Language subscale most strongly differentiated the groups. ADOS, ADI-R, and VABS-II scores did not differ. (2b) In the ASD group, there were no differences in ADOS scores, but multiplex-ASD children had higher ADI-R Communication scores than simplex-ASD children. Multiplex-ASD children tended to have lower MSEL and VABS-II scores than simplex children, particularly on the VABS-II motor scale, although these did not reach significance.

Conclusions: Results are consistent with previous reports of a twofold increase in ASD risk for multiplex siblings. In contrast with a study of school-age children with ASD (Cuccaro et al., 2003), we found evidence that multiplex children with and without ASD were somewhat more affected than simplex children. Within the no ASD group, these deficits were primarily characterized by lower developmental abilities. Findings may reflect an increased incidence of inherited risk variants in multiplex children that, while increasing the likelihood of atypical outcomes, may also be less specific to ASD. Further analyses will include longitudinal modeling of developmental trajectories in the first years of life to identify the earliest markers of atypical development in multiplex siblings. Results support the need for direct examination of genetic contributions to neurodevelopmental phenotypes of infant siblings.