Accumulating evidence suggests that corpus callosum development is critically involved in the emergence of behavioral and cognitive skills during the first two years of life and that structural abnormalities of the corpus callosum are associated with a variety of neurodevelopmental disorders. Indeed by adulthood ∼30% of individuals with agenesis of the corpus callosum (ACC), a congenital condition resulting in a partial or fully absent corpus callosum, exhibit phenotypic features consistent with autism spectrum disorder (ASD). However, very little is known about developmental similarities and/or differences among infants with ACC and infants who develop ASD. This study describes temperament in infants with ACC during the first year of life in comparison with a neurotypical control group. Additionally, it examines the potential contribution of disrupted callosal connectivity to early expression of temperament in ASD through comparison to children with high familial likelihood of ASD.

Longitudinal ratings of positive and negative emotionality were acquired at 6 and 12 months on the Infant Behavior Questionnaire-Revised across four groups of infants: isolated complete and partial ACC (n=104), high familial likelihood of ASD who do and do not have a confirmed ASD diagnosis (HL+ n=81, HL- n=282), and low-likelihood controls (LL- n=152).

Overall, the ACC group demonstrated blunted affect, with significantly lower positive and negative emotionality than LL controls at both timepoints. Specifically, the ACC group exhibited lower activity and approach dimensions of positive emotionality at both timepoints, with lower high-intensity pleasure at 6 months and lower vocal reactivity at 12 months. On negative emotionality subscales, the ACC group exhibited lower distress to limitations and sadness at both timepoints, as well as lower falling reactivity at 6 months. The ACC and HL groups did not differ significantly on positive emotionality at either timepoint. However, negative emotionality was lower in the ACC group than the HL- group at both timepoints and lower than the HL+ group at 12 months, with lower distress to limitations and sadness ratings than both HL groups at both timepoints.

These findings highlight the importance of interhemispheric connections in facilitating active engagement and pursuit of pleasurable activities during the first year of life, as well as expression of sadness and distress to limitations. Notably, similarities between infants with ACC and infants at elevated familial risk of ASD suggest that disrupted callosal connectivity may specifically contribute to reductions in positive emotionality.

Differences in adaptive functioning present early in development for many children with monogenic (Down Syndrome, Fragile X) and neurodevelopmental disorders. At this time, it is unclear whether children with ACC present with early adaptive delays, or if difficulties emerge later as functional tasks become more complex. While potential delays in motor development are frequently reported, other domains such as communication, social and daily living skills are rarely described. We used a prospective, longitudinal design to examine adaptive behavior from 6-24 months in children with ACC and compared their trajectories to those with monogenic and neurodevelopmental conditions.

Our sample included children with primary ACC (n= 27-47 depending on time point) whose caregivers completed the Vineland Adaptive Behavior Scales-Interview 3rd Edition, via phone at 6, 12, 18 and 24 months. Comparison samples (using the Vineland-2) included children with Down Syndrome (DS; n = 15-56), Fragile X (FX; n = 15-20), children at high familial likelihood for autism (HL-; n=192-280), and low likelihood (LL; no family history of autism and no developmental/behavioral diagnosis; n = 111196). A subset of the HL children received an autism diagnosis (HL+; n = 48-74). The DS group did not have an 18-month Vineland.

A series of linear mixed model analyses (using maximum likelihood) for repeated measures was used to compare groups on three Vineland domains at 6, 12, 18 and 24 month timepoints). All fixed factors (diagnostic group, timepoint, and group X timepoint interaction) accounted for significant variance on all Vineland domains (p < .001). Post hoc comparisons with Bonferroni-correction examined ACC Vineland scores compared to the other diagnostic groups at each timepoint. At 6 months, parent-ratings indicated the ACC group had significantly weaker skills than the LL group in Communication and Motor domains. At 12, 18 and 24 months, ratings revealed weaker Communication, Daily Living and Motor skills in the ACC group compared to both the LL and HL- groups. Compared to the other clinical groups, the ACC group had stronger Socialization and Motor skills than Fragile X at 6 months, and at 24 months had stronger Communication and Socialization skills than both the DS and FX groups, as well as stronger Socialization than the HL+ group.

Compared to children with low likelihood of ASD, children with primary ACC reportedly have weaker Communication and Motor skills from 6 to 24 months, with weakness in Daily Living Skills appearing at 12 months and all differences increase with age. Compared to Fragile X, the ACC exhibited relative strengths in socialization and motor skills starting at 6 months. By 24 months, the ACC group was outperforming the monogenic groups on Socialization and Communication. In general, the ACC scores were consistent with the HL+ sample, except the ACC group had stronger Social skills at 18 and 24 months. The results clearly inform the need for early intervention in the domains of motor and language skills. Additionally, as we know that children with ACC are at increased risk for social difficulties, research is needed both using more fine-grained social-communication tools, and following children from infancy through middle childhood.