Language disorders are highly heritable and are influenced by complex interactions between genetic and environmental factors. Despite more than twenty years of research, we still lack critical understanding of the biological underpinnings of language. This review provides an overview of the genetic landscape of developmental language disorders (DLD), with an emphasis on the importance of defining the specific features (the phenotype) of DLD to inform gene discovery. We review the specific phenotype of DLD in the genetic literature, and the influence of historic variation in diagnostic inclusion criteria on researchers’ ability to compare and replicate genotype–phenotype studies. This review provides an overview of the recently identified gene pathways in populations with DLD and explores current state-of-the-art approaches to genetic analysis based on the hypothesised architecture of DLD. We will show how recent global efforts to unify diagnostic criteria have vastly increased sample size and allow for large multi-cohort metanalyses, leading the identification of a growing number of contributory loci. We emphasise the important role of estimating the genetic architecture of DLD to decipher underlying genetic associations. Finally, we explore the potential for epigenetics and environmental interactions to further unravel the biological basis of language disorders.

Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions.   Methods: We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, CNTNAP2 and NRXN1, were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. Results: There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with CNTNAP2 or NRXN1 variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. Conclusions: We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in CNTNAP2 or NRXN1 are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. Stage 1 report: http://dx.doi.org/10.12688/wellcomeopenres.13828.2

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Worldwide, the majority of people prefer using the right hand for most motor tasks. Because of the link between handedness and language hemispheric dominance, handedness has been studied for association with language-related disorders. No clear pattern has emerged from these studies, and inconsistencies have been attributed to small sample sizes, publication bias, and heterogeneous criteria for the definition of handedness and disorders.Here, we assessed the frequency of non-right handedness (NRH) in 10 distinct cohorts not analysed before in this context. We identified N = 2,528 cases with reading and/or language impairment and N = 3,050 unique controls on the basis of a priori defined criteria. Overall, NRH was more frequent and more variable in the cases (8-24%) than in the controls (8-16%). Meta-analysis in the eight cohorts that met the inclusion criteria showed an increase of NRH in individuals with language/reading impairment compared to controls (OR = 1.21, CI = 1.03 - 1.44, p = 0.025). No moderator effects were detected for type of cohort (epidemiological versus clinical) and type of impairment (language versus reading). Our results support an association between NRH and reading and language impairments which could result from shared biological pathways underlying brain lateralization, handedness, and cognitive functions.

Purpose: Young people with developmental language disorder (DLD) have poorer mental health than those without DLD. However, not all young people with DLD are equally affected; some have more mental health difficulties than others. What explains these differences remains unclear. Method: Data from a community cohort study, the Avon Longitudinal Study of Parents and Children, were analyzed to investigate genetic and environmental influences on the development of mental health difficulties at five time points from childhood (7 years) to adolescence (16 years) in 6,387 young people (8.7% with DLD). Regression and latent class models were fitted to the data. Results: Polygenic scores (PGSs), indices of genetic risk, for common psychiatric disorders (major depressive disorder, anxiety disorder, and attention deficit hyperactivity disorder) predicted mental health difficulties in both groups (with and without DLD). The presence of DLD, in some instances, amplified mental health difficulties for those with high genetic risk for common psychiatric disorders. Subgroups of children with similar developmental trajectories of mental health difficulties were identified. Young people with DLD were more likely than those without DLD to follow mental health subgroups characterized by consistently high levels of difficulties during development. PGSs, socioeconomic status, and the early home environment distinguished subgroups with low mental health difficulties from those characterized by high levels of difficulties, but these effects did not differ based on DLD status. Conclusions: These findings suggest that, for the most part, both genetic and environmental risk affect the development of mental health difficulties in a cumulative way for young people with DLD (and those without). Some analysis did, however, suggest that genetic risk for common psychiatric disorders might manifest more strongly in those with DLD compared with those without DLD. Supplemental Material: https://doi.org/10.23641/asha.22351012