Toward epigenetic and gene regulation models of specific language impairment: looking for links among growth, genes, and impairments

Abstract

Children with specific language impairment (SLI) are thought to have an inherited form of language impairment that spares other developmental domains. SLI shows strong heritability and recent linkage and association studies have replicated results for candidate genes. Regulatory regions of the genes may be involved. Behavioral growth models of language development of children with SLI reveal that the onset of language is delayed, and the growth trajectories of children with SLI parallel those of younger children without SLI. The rate of language acquisition decelerates in the pre-adolescent period, resulting in immature language levels for the children with SLI that persist into adolescence and beyond. Recent genetic and epigenetic discoveries and models relevant to language impairment are reviewed. T cell regulation of onset, acceleration, and deceleration signaling are described as potential conceptual parallels to the growth timing elements of language acquisition and impairment. A growth signaling disruption (GSD) hypothesis is proposed for SLI, which posits that faulty timing mechanisms at the cellular level, intrinsic to neurocortical functioning essential for language onset and growth regulation, are at the core of the growth outcomes of SLI. The GSD highlights the need to document and account for growth patterns over childhood and suggests needed directions for future investigation.

The remarkable ability of young humans to acquire speech and language, without explicit tutoring, during the preschool years is an unsolved mystery. Debates have swirled around the relative contributions of nature and nurture. Although uniquely linguistic innate abilities have long been assumed by some scholars and challenged by others, until recently explicit genetic investigation was not attempted. A first wave of candidate gene discoveries has been reported recently for language, speech and reading impairments in children and their families. A recent special issue of this journal, published in December 2011, focused on epigenetics for studies of the etiology of language, speech, and reading impairments. Epigenetics, referring to mechanisms ‘above’ the genome, involves modifications of DNA or associated proteins, other than DNA sequence variation, that carry information content during cell division. The epigenome consists of chemical compounds that modify, or mark, the genome in a way that tells it what to do, where to do it, and when to do it. Epigenetic marks, not part of the DNA itself, can be passed on from cell to cell as cells divide, and from one generation to the next [1]. This level of genetics inquiry would be a new direction that could build on and clarify the recent candidate gene discoveries reported for language, speech, and reading impairments, or shift attention to new mechanisms of gene regulation. The collection of papers in the special issue covered the following: the role of epigenetic modifications underlying the developmental consequences of early life events [2], recent candidate gene investigations, possible phenotypic interrelationships, and challenges for interpretation [3-5], a call for phenotypes at the level of neuronal pathways and local brain circuits involved in speech and language processing for the next generation of genetics/epigenetics investigation [6], and how the effects of cochlear implants on deaf children’s language acquisition depend on the age of implant, suggesting possible epigenetic influences [7].

This paper takes up the theme of epigenetics and other possible regulatory genetic mechanisms in the context of the phenotypes associated with specific language impairment (SLI), a condition with genetic influences. Language change over time in children with SLI demonstrates both weaknesses and strengths, tied to age-related phases of language acquisition. The key concept here is the timing of language growth, with suggestions about how regulatory mechanisms, epigenetic and genetic, may provide clarifications of timed genetic effects that play out as delays and long-term deficits in language, in cascades of phenotypic outcomes.

The present review unfolds in five main sections. The first three sections focus on the behavioral phenotypes of SLI. The first section provides a brief description of the speech and language phenotypes associated with children with SLI, with the exclusionary criteria intrinsic to the diagnosis. The second section provides an overview of the ways in which language grows over time in children with and without SLI, and the issues of interpretation that arise from the findings. The third section highlights new questions generated from the growth findings, questions that call to mind possible biological underpinnings of a growth drivetrain for language acquisition. The fourth and fifth sections provide a selective summary of candidate gene discoveries for language impairment, followed by a discussion of epigenetic models relevant to language acquisition and impairment and consideration of possible mechanisms involved in the three elements of language growth in SLI: delayed onset, acceleration, and premature deceleration. A growth signaling dysfunction model of SLI is proposed, with implications for future investigation.