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

N Marrus,For The Ibis Network ,J Piven,A T Eggebrecht,J R Pruett,J N Constantino,A M Estes,H C Hazlett,J Parish-Morris,J J Wolff,M R Swanson,S Dager,L P Hall,R T Schultz,L Zwaigenbaum,S J Paterson,K N Botteron,J T Elison

doi:10.1186/s11689-018-9247-8

Abstract

BackgroundLanguage 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.MethodsWe 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.ResultsMeta-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.ConclusionsGreater 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.

Highlights

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
The Mantel-Haenszel test, which allowed pooling of participants across these studies, showed that HR-noASD siblings were 4.17 times more likely to experience language delay than LR-noASD siblings [χ2MH(1) = 14.62, p < .001; LR-noASD 6.0% language delay; HR-noASD 21.0% language delay]
For five of the studies (Table 1), comparison of early language ability between HR-noASD and LR-noASD siblings was possible based on continuous scores from the Mullen Scales of Early Learning (MSEL)

Summary

Introduction

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. Endophenotypes demonstrate several criteria involving inheritance among family members with and without the disorder These criteria include co-segregating, or being inherited more commonly, in affected versus unaffected family members and aggregating, or occurring with increased frequency, in unaffected family members versus the general population, which is at lower genetic risk [1, 2]. The occurrence of these familial patterns in the context of a heritable trait substantiates the relationship between an endophenotype and genetic factors for a given disorder. Because endophenotypes can be inferred to reflect causal pathways of a disorder and can be reliably measured in individuals with and without the disorder [1, 2], they enhance the sensitivity to determine contributory genes and, by extension, the underlying biology

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