Characterization of Infants at High-Risk and Ultra High-Risk for Autism

Background:  Converging evidence suggests that there are multiple genetic pathways to autism spectrum disorder (ASD). One genetically 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). These younger siblings (high-risk [HR] siblings) have a recurrence rate of 18.7%, whereas siblings from multiplex families (i.e., ultra high-risk [UHR] siblings) carry an additional twofold increase in risk. While it is expected that a larger proportion of UHR siblings will present with atypical development by age three, the timing and quality of the divergence in development between UHR and HR siblings is unclear. Investigation of UHR siblings offers a unique opportunity to determine whether there are observable differences in early development associated with a heightened genetic load for ASD.

Objectives: To contrast cognitive abilities, language skills, and early autism symptoms in UHR and HR siblings from ages 6-18 months.

Methods: Participants included 25 HR and 9 UHR siblings enrolled in a longitudinal study. HR siblings had one older sibling with ASD (no other family history) and UHR siblings had at least two older siblings with ASD. Cognitive abilities were measured by the Mullen Scales of Early Learning (MSEL) at 6, 12, and 18 months. Language skills were measured with the MacArthur Communication Development Inventory (CDI; parent report) at 9, 12, and 18 months. Early ASD symptoms were measured by the Autism Observation Scale for Infants (AOSI) at 12 months and Autism Diagnostic Observation Schedule-Toddler Module (ADOS-T) at 18 months.

Results: Initial results (see Table 1) indicate no apparent differences in cognitive and language abilities between HR and UHR siblings prior to one year, nor were there differences in gross motor skills at any age. However, differences were observed in cognitive abilities at 12 and 18 months. Group differences were most prominent in the MSEL nonverbal domains at 12 months, while global cognitive delays, particularly in language, characterized the UHR siblings’ MSEL performance at 18 months. Differences in language skills were also reported by parents on the CDI, most notably in the number of words produced at 12 and 18 months. There were no differences in early autism symptoms at 12 or 18 months.

Conclusions: This study found clinically significant differences in cognitive and language abilities between HR and UHR siblings emerging by 12 months. Children from multiplex families had lower cognitive scores, with a higher incidence of scores indicating developmental delays at 18 months. Although preliminary, results suggest that the impact of increased genetic load associated with multiplex family status may first become evident in general developmental delays, rather than early ASD symptomatology. This may reflect an increased incidence of inherited risk variants in UHR siblings that, while increasing disease burden, may also be less specific to ASD. Given the high incidence of developmental delays, UHR siblings should be monitored closely to assess the need for early intervention. Longitudinal data will continue to be collected in this sample.