Dr Hayley Mountford

The negative health effects cigarette smoking during pregnancy (SDP) on the foetus are well known. Despite previous reports of poor cognitive performance in offspring exposed to SDP, few studies specifically consider language outcomes according to maternal smoking. In this study, we systematically review the literature to assess the relationships between SDP and child language. Of the 14 studies reviewed, 13 (93%) reported significant associations between maternal smoking or exposure and language outcomes. Despite this consistent association, only 8 of the 13 studies reporting associations (62%) concluded direct relationships between exposure and outcome. The remaining studies suggested that the relationship between smoking and language could be explained by factors such as maternal IQ, socioeconomic status (SES) and parental age. Future studies should apply careful study designs allowing for confounding factors across child, parental, environmental and genetic influences. Our review suggests that smoking cessation is likely to positively affect child language outcomes.

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 hypothesized 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 emphasize 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.  

Autism spectrum disorders (ASD) are neurodevelopmental disorders with an estimated heritability of >60%. Family‐based genetic studies of ASD have generally focused on multiple small kindreds, searching for de novo variants of major effect. We hypothesized that molecular genetic analysis of large multiplex families would enable the identification of variants of milder effects. We studied a large multigenerational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP). We identified a rare heterozygous variant in the gene encoding 1,4‐ɑ‐glucan branching enzyme 1 (GBE1) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP, and none of four tested unaffected individuals. We genotyped a community‐acquired cohort of 389 individuals with ASD and identified three additional probands. Cascade analysis demonstrated that the variant was present in 11
of 13 individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. The variant was not enriched in the combined UK10K ASD cohorts of European ancestry but heterozygous GBE1 deletion was overrepresented in large ASD cohorts, collectively suggesting an association between GBE1 and ASD.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Robinson Crusoe Island is a geographically and socially isolated settlement located over 600km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (TEL) has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis. 

Here we utilise whole-genome sequencing to investigate potential underlying variants in a panel of thirty-four genes known to play a role in language disorders, in seven TEL affected and ten unaffected islanders. We use this targeted approach to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. We go on to test whether the overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. 

In the absence of explanatory rare variants, we further investigate these candidate genes within a complex model of inheritance, where inheriting a small number of moderate impact common variants may increase susceptibility of developing TEL. We examine if any variants segregate with affection status or with founder-brother-related status, and therefore may increase risk of developing a language disorder. Finally, we perform a pooled, gene-based tests to evaluate relationships between combined variation across candidate genes and TEL affection status.

Here we report a comprehensive examination of genes directly implicated in language-related mechanisms to identify ‘low hanging fruit’ of causative monogenic Mendelian variants, and complex association model of increased susceptibility in developmental language disorder found on Robinson Crusoe Island.

Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism.

Methods/results

High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient’s distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them.

Conclusions

This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.