Language delay aggregates in toddler siblings of children with autism spectrum disorder

Abstract

Background: Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype.

Methods: We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample.

Results: Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n = 235) versus LR-noASD group (n = 115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition.

Conclusions: Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms.

Keywords: Autism spectrum disorder; Development; Endophenotype; Infant sibling; Language.

Fig. 1

Meta-analysis of language scores in high-risk siblings without ASD. Forest plots display the results of the meta-analysis examining differences in receptive and expressive language scores between low-risk siblings without ASD (LR-noASD) and high-risk siblings without ASD (HR-noASD). Circle sizes illustrate each study’s weighted impact when including IBIS data, with values for weights and effect sizes listed on the right. Error bars represent 95% confidence intervals (CI). Summary weighted effect sizes for published studies only, indicated as “Overall (literature only),” are shown as a light gray diamond; the dark gray diamonds show the result including IBIS data. Numbers of subjects in HR-noASD (HR) and LR-noASD (LR) groups are adjacent to these diamond markers. Both summary effect sizes indicate that receptive and expressive language scores are significantly lower in HR-noASD siblings. The effect size is moderate for receptive language and small for expressive language

Fig. 2

Language scores at 24 months of age in IBIS infant siblings. Histograms display a wide distribution of T-scores for Mullen expressive and receptive language scores in the Infant Brain Imaging Study among both the low-risk siblings without ASD (LR-noASD) and high-risk siblings without ASD (HR-noASD). HR-noASD siblings (black bars) generally show a larger percentage of individuals in bins for lower scores, whereas LR-noASD sibling (gray bars) show a larger percentage of individuals in bins with higher scores, signifying a pathological shift in the distribution for the high-risk group