Correction: Exome Sequencing in an Admixed Isolated Population IndicatesNFXL1 Variants Confer a Risk for Specific Language Impairment

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model

Defining the molecular architecture of language networks

The ability to use language is a uniquely human trait involving one of the most complex and poorly understood biological processes. This is particularly true when considering the encoding of human language at the molecular level. Disorders of speech and language are highly heritable and widely prevalent in the general population. Approximately 7% of school age children display specific language impairment (SLI) and language deficiencies are known to feature in a range of common neurodevelopmental disorders such as autism spectrum disorders. The first direct insights into the molecular basis of language were given by the identification of the FOXP2 gene. Mutations in this gene were shown to be causative of a rare speech and language disorder in a large pedigree. Since then, a number of FOXP2 disruptions in unrelated patients displaying a similar phenotype have been reported. However FOXP2 remains the only known monogenic cause of language disorder and little progress has been made via traditional genetic approaches to understanding the molecular basis of language and language impairment. Given that FOXP2 acts as a transcription factor to regulate target gene expression, we hypothesized that understanding the downstream regulatory pathways would give insight into the molecular basis of normal language development and language disorder. We have identified gene networks regulated by FOXP2 that have been implicated in language development and demonstrated that new candidates for involvement in common language disorders can be found by identifying genes that act in these pathways. Our recent findings modeling Foxp2 pathways in the brain, suggest that neuronal connectivity and circuit formation is disturbed in particular types of language disorder due to neurite outgrowth defects during development. We are currently studying how effects on this and other FOXP2 related pathways that we have identified (including Wnt signalling and non-coding RNA pathways) are involved in neural circuit formation and language development, and investigating genetic risk factors from these pathways in patients via genome based screening studies. This novel approach will help us to understand the fundamental neurodevelopmental basis of language and pinpoint genetic risk factors for language impairments

Defining the molecular architecture of language networks

The ability to use language is a uniquely human trait involving one of the most complex and poorly understood biological processes. This is particularly true when considering the encoding of human language at the molecular level. Disorders of speech and language are highly heritable and widely prevalent in the general population. Approximately 7% of school age children display specific language impairment (SLI) and language deficiencies are known to feature in a range of common neurodevelopmental disorders such as autism spectrum disorders. The first direct insights into the molecular basis of language were given by the identification of the FOXP2 gene. Mutations in this gene were shown to be causative of a rare speech and language disorder in a large pedigree. Since then, a number of FOXP2 disruptions in unrelated patients displaying a similar phenotype have been reported. However FOXP2 remains the only known monogenic cause of language disorder and little progress has been made via traditional genetic approaches to understanding the molecular basis of language and language impairment. Given that FOXP2 acts as a transcription factor to regulate target gene expression, we hypothesized that understanding the downstream regulatory pathways would give insight into the molecular basis of normal language development and language disorder. We have identified gene networks regulated by FOXP2 that have been implicated in language development and demonstrated that new candidates for involvement in common language disorders can be found by identifying genes that act in these pathways. Our recent findings modeling Foxp2 pathways in the brain, suggest that neuronal connectivity and circuit formation is disturbed in particular types of language disorder due to neurite outgrowth defects during development. We are currently studying how effects on this and other FOXP2 related pathways that we have identified (including Wnt signalling and non-coding RNA pathways) are involved in neural circuit formation and language development, and investigating genetic risk factors from these pathways in patients via genome based screening studies. This novel approach will help us to understand the fundamental neurodevelopmental basis of language and pinpoint genetic risk factors for language impairments

A novel approach reveals first molecular networks in the bat brain: implications for vocal communication

Bats are able to employ an astonishin- gly complex vocal repertoire for navigating their environment and conveying social information. A handful of species also show evidence for vocal learning, an extremely rare ability shared only with humans and few other animals. However, despite their obvious potential for the study of vocal communication, bats remain severely understudied at a molecular level. To address this fundamental gap we performed the first transcriptome profiling and genetic interrogation of molecular networks in the brain of a highly vo- cal bat species, P. discolor. To identify functional, biologically relevant gene networks, we utilized two contrasting co-expression network analysis methods with distinct underlying algorithms; WGCNA and MCLUST. These methods typically need large sample sizes for correct clustering, which can be prohibitive where samples are limited, such as in this study. To overcome this, we built on the WGCNA and MCLUST methods to develop a novel approach for identifying robust co-expression gene networks using few samples (≤6). Using this approach, we were able to ge- nerate tissue-specific functional gene networks from the bat PAG, a brain region fundamental for mammalian vocalization. The most highly connected of the networks identified in our study represented a cluster of genes involved in glu- tamatergic synaptic transmission. Glutamatergic signaling plays an essential role in vocalizations elicited from the PAG, suggesting that the gene network uncovered here is mechanistically impor - tant for vocal-motor control in mammals. These findings show that our innovative gene clustering approach can reveal robust biologically relevant gene co-expression networks with limited sample sizes. Moreover, this work reports the first gene network analysis performed in a bat brain and establishes P. discolor as a novel, tractable model system for understanding the genetics of vocal communication

Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy and language impairment

Background Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also common in the normal population. Conversely, homozygous mutations are rare and have not been found in unaffected individuals. Case presentation We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Affected family members show epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype. Conclusions We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development