Publications

Abstract

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late
life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438
adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were
also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height.
We found a high genetic correlation with child head circumference (genetic = 0.748), which indicates a similar genetic
background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial
volume were also related to childhood and adult cognitive function, and Parkinson’s disease, and were enriched near genes
involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial
volume and provide genetic support for theories on brain reserve and brain overgrowth.

Abstract

Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype–phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations.

Abstract

Recent genome wide association scans (GWAS) for reading and language abilities have pin-pointed promising new candidate loci. However, the potential contributions of these loci remain to be validated. In the present study, we tested 17 of the most significantly associated single nucleotide polymorphisms (SNPs) from these GWAS studies (p < 10−6 in the original studies) in a new independent population dataset from the Netherlands: known as FIOLA (Familial Influences On Literacy Abilities). This dataset comprised 483 children from 307 nuclear families, plus 505 adults (including parents of participating children), and provided adequate statistical power to detect the effects that were previously reported. The following measures of reading and language performance were collected: word reading fluency, nonword reading fluency, phonological awareness, and rapid automatized naming. Two SNPs (rs12636438, rs7187223) were associated with performance in multivariate and univariate testing, but these did not remain significant after correction for multiple testing. Another SNP (rs482700) was only nominally associated in the multivariate test. For the rest of the SNPs we did not find supportive evidence of association. The findings may reflect differences between our study and the previous investigations in respects such as the language of testing, the exact tests used, and the recruitment criteria. Alternatively, most of the prior reported associations may have been false positives. A larger scale GWAS meta-analysis than those previously performed will likely be required to obtain robust insights into the genomic architecture underlying reading and language.

Abstract

Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans.

Abstract

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes

Abstract

Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2, and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo.

Abstract

Individuals with heterozygous 16p11.2 deletions reportedly suffer from a variety of difficulties with speech and language. Indeed, recent copy-number variant screens of children with childhood apraxia of speech (CAS), a specific and rare motor speech disorder, have identified three unrelated individuals with 16p11.2 deletions. However, the nature and prevalence of speech and language disorders in general, and CAS in particular, is unknown for individuals with 16p11.2 deletions. Here we took a genotype-first approach, conducting detailed and systematic characterization of speech abilities in a group of 11 unrelated children ascertained on the basis of 16p11.2 deletions. To obtain the most precise and replicable phenotyping, we included tasks that are highly diagnostic for CAS, and we tested children under the age of 18 years, an age group where CAS has been best characterized. Two individuals were largely nonverbal, preventing detailed speech analysis, whereas the remaining nine met the standard accepted diagnostic criteria for CAS. These results link 16p11.2 deletions to a highly penetrant form of CAS. Our findings underline the need for further precise characterization of speech and language profiles in larger groups of affected individuals, which will also enhance our understanding of how genetic pathways contribute to human communication disorders.

Abstract

The rise of genomic technologies has yielded exciting new routes for studying the biological foundations of language. Researchers have begun to identify genes implicated in neurodevelopmental disorders that disrupt speech and language skills. This chapter illustrates how such work can provide powerful entry points into the critical neural pathways using FOXP2 as an example. Rare mutations of this gene cause problems with learning to sequence mouth movements during speech, accompanied by wide-ranging impairments in language production and comprehension. FOXP2 encodes a regulatory protein, a hub in a network of other genes, several of which have also been associated with language-related impairments. Versions of FOXP2 are found in similar form in many vertebrate species; indeed, studies of animals and birds suggest conserved roles in the development and plasticity of certain sets of neural circuits. Thus, the contributions of this gene to human speech and language involve modifications of evolutionarily ancient functions.

Abstract

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders

Abstract

Adult mouse ultrasonic vocalizations (USVs) occur in multiple behavioral and stimulus contexts associated with various levels of arousal, emotion, and social interaction. Here, in three experiments of increasing stimulus intensity (water; female urine; male interacting with adult female), we tested the hypothesis that USVs of adult males express the strength of arousal and emotion via different USV parameters (18 parameters analyzed). Furthermore, we analyzed two mouse lines with heterozygous Foxp2 mutations (R552H missense, S321X nonsense), known to produce severe speech and language disorders in humans. These experiments allowed us to test whether intact Foxp2 function is necessary for developing full adult USV repertoires, and whether mutations of this gene influence instinctive vocal expressions based on arousal and emotion. The results suggest that USV calling rate characterizes the arousal level, while sound pressure and spectro-temporal call complexity (overtones/harmonics, type of frequency jumps) may provide indices of levels of positive emotion. The presence of Foxp2 mutations did not qualitatively affect the USVs; all USV types that were found in wild-type animals also occurred in heterozygous mutants. However, mice with Foxp2 mutations displayed quantitative differences in USVs as compared to wild-types, and these changes were context dependent. Compared to wild-type animals, heterozygous mutants emitted mainly longer and louder USVs at higher minimum frequencies with a higher occurrence rate of overtones/harmonics and complex frequency jump types. We discuss possible hypotheses about Foxp2 influence on emotional vocal expressions, which can be investigated in future experiments using selective knockdown of Foxp2 in specific brain circuits.

Abstract

Background

Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs).
Methods

In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV−), and we analyzed continuous probe intensity data using FamCNV.
Results

No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10−2–10−3) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026–0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10−2–10−4) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls.
Conclusions

These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.

Abstract

The inhibitory mechanisms that prevent gene expression programs from one tissue to be expressed in another are poorly understood. Foxp1/2/4 are forkhead transcription factors that repress gene expression and are individually important for endoderm development. We show that combined loss of all three Foxp1/2/4 family members in the developing anterior foregut endoderm leads to a loss of lung endoderm lineage commitment and subsequent development. Foxp1/2/4 deficient lungs express high levels of transcriptional regulators not normally expressed in the developing lung, including Pax2, Pax8, Pax9 and the Hoxa9-13 cluster. Ectopic expression of these transcriptional regulators is accompanied by decreased expression of lung restricted transcription factors including Nkx2-1, Sox2, and Sox9. Foxp1 binds to conserved forkhead DNA binding sites within the Hoxa9-13 cluster, indicating a direct repression mechanism. Thus, Foxp1/2/4 are essential for promoting lung endoderm development by repressing expression of non-pulmonary transcription factors

Abstract

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

Abstract

s Metrics Comments Related Content Abstract Introduction Materials and Methods Results Discussion Supporting Information Acknowledgments Author Contributions References Reader Comments (0) Media Coverage Figures Abstract Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.

Abstract

Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.

Abstract

BACKGROUND:
Synaesthesia is a neurodevelopmental condition in which a sensation in one modality triggers a perception in a second modality. Autism (shorthand for Autism Spectrum Conditions) is a neurodevelopmental condition involving social-communication disability alongside resistance to change and unusually narrow interests or activities. Whilst on the surface they appear distinct, they have been suggested to share common atypical neural connectivity.

METHODS:
In the present study, we carried out the first prevalence study of synaesthesia in autism to formally test whether these conditions are independent. After exclusions, 164 adults with autism and 97 controls completed a synaesthesia questionnaire, autism spectrum quotient, and test of genuineness-revised (ToG-R) online.

RESULTS:
The rate of synaesthesia in adults with autism was 18.9% (31 out of 164), almost three times greater than in controls (7.22%, 7 out of 97, P <0.05). ToG-R proved unsuitable for synaesthetes with autism.

CONCLUSIONS:
The significant increase in synaesthesia prevalence in autism suggests that the two conditions may share some common underlying mechanisms. Future research is needed to develop more feasible validation methods of synaesthesia in autism.

Abstract

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10−9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.

Abstract

Dyslexia is a highly heritable learning disorder with a complex underlying genetic architecture. Over the past decade, researchers have pinpointed a number of candidate genes that may contribute to dyslexia susceptibility. Here, we provide an overview of the state of the art, describing how studies have moved from mapping potential risk loci, through identification of associated gene variants, to characterization of gene function in cellular and animal model systems. Work thus far has highlighted some intriguing mechanistic pathways, such as neuronal migration, axon guidance, and ciliary biology, but it is clear that we still have much to learn about the molecular networks that are involved. We end the review by highlighting the past, present, and future contributions of the Dutch Dyslexia Programme to studies of genetic factors. In particular, we emphasize the importance of relating genetic information to intermediate neurobiological measures, as well as the value of incorporating longitudinal and developmental data into molecular designs

Abstract

Next-generation sequencing is set to transform the discovery of genes underlying neurodevelopmental disorders, and so off er important insights into the biological bases of spoken language. Success will depend on functional assessments in neuronal cell lines, animal models and humans themselves.

Abstract

State-of-the-art DNA sequencing is providing ever more detailed insights into the genomes of humans, extant apes, and even extinct hominins (1–3), offering unprecedented opportunities to uncover the molecular variants that make us human. A common assumption is that the emergence of behaviorally modern humans after 200,000 years ago required—and followed—a specific biological change triggered by one or more genetic mutations. For example, Klein has argued that the dawn of human culture stemmed from a single genetic change that “fostered the uniquely modern ability to adapt to a remarkable range of natural and social circumstance” (4). But are evolutionary changes in our genome a cause or a consequence of cultural innovation (see the figure)?

Abstract

First paragraph: The study of the transmission of sign languages can give novel insights into the transmission of spoken languages1 and, more generally, into gene–culture coevolution. Over the years, several papers related to the persistence of sign language have been
reported.2–6 All of these studies have emphasized the role of assortative (non-random) mating by deafness state (ie, a tendency for deaf individuals to partner together) for increasing the frequency of recessive deafness, and hence for the persistence of sign language in a population.

Abstract

Researchers are beginning to uncover the neurogenetic pathways that underlie our unparalleled capacity for spoken language. Initial clues come from identification of genetic risk factors implicated in developmental language disorders. The underlying genetic architecture is complex, involving a range of molecular mechanisms. For example, rare protein-coding mutations of the FOXP2 transcription factor cause severe problems with sequencing of speech sounds, while common genetic risk variants of small effect size in genes like CNTNAP2, ATP2C2 and CMIP are associated with typical forms of language impairment. In this article, we describe how investigations of these and other candidate genes, in humans, animals and cellular models, are unravelling the connections between genes and cognition. This depends on interdisciplinary research at multiple levels, from determining molecular interactions and functional roles in neural cell-biology all the way through to effects on brain structure and activity.

Abstract

Absolute pitch and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in a same individual. Here we systematically evaluate the occurrence of syesthesia in a population of 768 subjects with documented absolute pitch. Out of these 768 subjects, 151(20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with absolute pitch and 36 multiplex families with synesthesia. We observed a peak NPL LOD=4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2 using a dominant model. These data establish the close phenotypic and genetic relationship between absolute pitch and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.

Abstract

In this issue, Raca et al1 present two cases of childhood apraxia of speech (CAS) arising from microdeletions of chromosome 16p11.2. They propose that comprehensive phenotypic profiling may assist in the delineation and classification of such cases. To complement this study, we would like to report on a third, unrelated, child who presents with CAS and a chromosome 16p11.2 heterozygous deletion. We use genetic data from this child and his family to illustrate how comprehensive genetic profiling may also assist in the characterisation of 16p11.2 microdeletion syndrome.

Abstract

Disorders of speech and language are highly heritable, providing strong
support for a genetic basis. However, the underlying genetic architecture is complex,
involving multiple risk factors. This chapter begins by discussing genetic loci associated
with common multifactorial language-related impairments and goes on to
detail the only gene (known as FOXP2) to be directly implicated in a rare monogenic
speech and language disorder. Although FOXP2 was initially uncovered in
humans, model systems have been invaluable in progressing our understanding of
the function of this gene and its associated pathways in language-related areas of the
brain. Research in species from mouse to songbird has revealed effects of this gene
on relevant behaviours including acquisition of motor skills and learned vocalisations
and demonstrated a role for Foxp2 in neuronal connectivity and signalling,
particularly in the striatum. Animal models have also facilitated the identification of
wider neurogenetic networks thought to be involved in language development and
disorder and allowed the investigation of new candidate genes for disorders involving
language, such as CNTNAP2 and FOXP1. Ongoing work in animal models promises
to yield new insights into the genetic and neural mechanisms underlying human
speech and language

Abstract

Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.