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Faraneh Vargha-khadem - One of the best experts on this subject based on the ideXlab platform.
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Functional MRI abnormalities during covert speech associated with FOXP2 gene mutation
2020Co-Authors: Frederique Liegeois, Alan Connelly, M Mishkin, D G Gadian, Torsten Baldeweg, Faraneh Vargha-khademAbstract:Half the members of the KE Family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoKEn) verb generation and word repetition. The unaffected Family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.
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Neocerebellar Crus I Abnormalities Associated with a Speech and Language Disorder Due to a Mutation in FOXP2
The Cerebellum, 2019Co-Authors: G. P. D. Argyropoulos, M Mishkin, K. E. Watkins, E. Belton-pagnamenta, F. Liégeois, K. S. Saleem, Faraneh Vargha-khademAbstract:Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the ‘KE Family’, who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene’s early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with KEy aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech.
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Phonological Working Memory and FOXP2
Neuropsychologia, 2017Co-Authors: Katrin Schulze, Faraneh Vargha-khadem, Mortimer MishkinAbstract:Abstract The discovery and description of the affected members of the KE Family (aKE) initiated research on how genes enable the unique human trait of speech and language. Many aspects of this genetic influence on speech-related cognitive mechanisms are still elusive, e.g. if and how cognitive processes not directly involved in speech production are affected. In the current study we investigated the effect of the FOXP2 mutation on Working Memory (WM). Half the members of the multigenerational KE Family have an inherited speech-language disorder, characterised as a verbal and orofacial dyspraxia caused by a mutation of the FOXP2 gene. The core phenotype of the affected KE members (aKE) is a deficiency in repeating words, especially complex non-words, and in coordinating oromotor sequences generally. Execution of oromotor sequences and repetition of phonological sequences both require WM, but to date the aKE's memory ability in this domain has not been examined in detail. To do so we used a test series based on the Baddeley and Hitch WM model, which posits that the central executive (CE), important for planning and manipulating information, works in conjunction with two modality-specific components: The phonological loop (PL), specialized for processing speech-based information; and the visuospatial sKEtchpad (VSSP), dedicated to processing visual and spatial information. We compared WM performance related to CE, PL, and VSSP function in five aKE and 15 healthy controls (including three unaffected members of the KE Family who do not have the FOXP2 mutation). The aKE scored significantly below this control group on the PL component, but not on the VSSP or CE components. Further, the aKE were impaired relative to the controls not only in motor (i.e. articulatory) output but also on the recognition-based PL subtest (word-list matching), which does not require speech production. These results suggest that the aKE's impaired phonological WM may be due to a defect in subvocal rehearsal of speech-based material, and that this defect may be due in turn to compromised speech-based representations.
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The speech gene FOXP2 is not imprinted
Journal of Medical Genetics, 2012Co-Authors: Anna Thomas, Faraneh Vargha-khadem, Jennifer M. Frost, Miho Ishida, Gudrun E. Moore, Philip StanierAbstract:The Forkhead-box protein P2 ( FOXP2 ) was the first gene to be linKEd to an inherited form of speech and language disorder, described as developmental verbal dyspraxia (DVD).1 In this study a point mutation was described in a three generation ‘KE’ Family displaying autosomal dominant inheritance, while an unrelated but similar patient ‘CS’, had a translocation breakpoint at the same locus1. A subsequent report, described a series of patients with chromosomal anomalies involving FOXP2 that were inherited with parent specific origins. Although unconfirmed, this data strongly suggested that FOXP2 was liKEly to be maternally imprinted and therefore paternally expressed.2 Subsequently, these findings have been described as evidence supporting a theoretical role for imprinting in the evolution of language.3 DVD reflects impaired selection and sequencing of the orofacial muscle movements required for correctly articulating speech. Affected individuals have inherent problems with linguistic and grammatical processing, struggling to pronounce words, sounds and syllables correctly. FOXP2 is a transcriptional repressor that is widely distributed in the fetal and adult brain (as well as other tissues) where it is thought to regulate the expression of genes in the cortical, basal ganglia and cerebellar circuits.4 This gene has been of huge interest with evidence suggesting that evolutionary selection of FOXP2 has taKEn place in the human to …
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Endophenotypes of FOXP2: Dysfunction within the human articulatory network
European Journal of Paediatric Neurology, 2011Co-Authors: Frederique Liegeois, Angela T Morgan, Alan Connelly, Faraneh Vargha-khademAbstract:Abstract The identification of the first gene involved in a speech-language disorder was made possible through the study of a British multi-generational Family (the “KE Family”) in whom half the members have an inherited speech-language disorder caused by a FOXP2 mutation. Neuroimaging investigations in the affected members of the KE Family have revealed structural and functional abnormalities in a wide cortical-subcortical network. Functional imaging studies have confirmed dysfunction of this network by revealing abnormal activation in several areas including Broca’s area and the putamen during language-related tasks, such as word repetition and generation. Repeating nonsense words is particularly challenging for the affected members of the Family, as well as in other individuals suffering from idiopathic developmental specific language impairments; yet, thus far the neural correlates of the nonword repetition task have not been examined in individuals with developmental speech and language disorders. Here, four affected members of the KE Family and four unrelated age-matched healthy participants repeated nonsense words aloud during functional MRI scanning. Relative to control participants, repetition in the affected members was severely impaired, and brain activation was significantly reduced in the premotor, supplementary and primary motor cortices, as well as in the cerebellum and basal ganglia. We suggest that nonword repetition is the optimal endophenotype for FOXP2 disruption in humans because this task recruits brain regions involved in the imitation and vocal learning of novel sequences of speech sounds.
Simon E. Fisher - One of the best experts on this subject based on the ideXlab platform.
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The Genetic Basis of a Severe Speech and Language Disorder
Research and Perspectives in Neurosciences, 2020Co-Authors: Simon E. FisherAbstract:The KE Family represent the only documented case of single-gene inheritance of a speech and language disorder. There has been some debate over the specificity of their impairment and the precise nature of the core deficit. Nevertheless, it is generally agreed that the gene that is disrupted in affected members of this family must play a KEy role in neurological mechanisms that are important for speech and language acquisition. The simple transmission pattern of the difficulties in the KE Family allowed geneticists to use a traditional strategy to map the gene responsible to a small interval on chromosome 7. They then exploited data from large-scale human genomic sequencing efforts to assemble a detailed map of genes in this chromosomal region. A child was identified (unrelated to the KE Family) who has speech and language disorder associated with a gross chromosomal abnormality involving the candidate region of chromosome 7. It was demonstrated that the abnormality in this child directly interrupts a novel gene encoding a polyglutamine repeat and a forkhead/winged-helix DNA-binding domain. The gene, known as FOXP2, is strongly expressed in the developing brain during embryogenesis and belongs to a large Family of transcription factors involved in switching on and off other genes. Mutation screening of FOXP2 in the KE Family revealed a point mutation in all affected individuals, which leads to alteration of a KEy residue in the DNA-binding domain, and is predicted to disrupt the function of the protein. In the future, studies of FOXP2 may provide a unique entry-point for investigating molecular processes mediating speech and language development.
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A Foxp2 Mutation Implicated in Human Speech Deficits Alters Sequencing of Ultrasonic Vocalizations in Adult Male Mice
Frontiers in Behavioral Neuroscience, 2016Co-Authors: Jonathan Chabout, Simon E. Fisher, Abhra Sarkar, Sheel R. Patel, Taylor Radden, David B. Dunson, Erich D. JarvisAbstract: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.
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identification of foxp2 truncation as a novel cause of developmental speech and language deficits
American Journal of Human Genetics, 2005Co-Authors: Kay D Macdermot, F Varghakhadem, Elena Bonora, Nuala Sykes, Anne Marie Coupe, Sonja C Vernes, Fiona Haslam Mckenzie, Robert L Smith, Anthony P Monaco, Simon E. FisherAbstract:FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE Family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE Family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.
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A forkhead-domain gene is mutated in a severe speech and language disorder
Nature, 2001Co-Authors: Simon E. Fisher, Faraneh Vargha-khadem, Jane A. Hurst, Anthony P MonacoAbstract:Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity^ 1 . Although studies of twins consistently indicate that a significant genetic component is involved^ 1 , 2 , 3 , most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait^ 4 . Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5 ). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval^ 6 . Here we show that the gene FOXP2 , which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE Family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.
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The SPCH1 region on human 7q31: Genomic characterization of the critical interval and localization of translocations associated with speech and language disorder
American Journal of Human Genetics, 2000Co-Authors: Simon E. Fisher, Jane A. Hurst, Elaine R. Levy, Shirley Hodgson, Stephen Jeremiah, Susan Povey, D. Curtis Jamison, Eric D. GreenAbstract:The KE Family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE Family with 120 of these STSs (average spacing 3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE Family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language.
Kate E Watkins - One of the best experts on this subject based on the ideXlab platform.
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Gene Expression to Neurobiology and Behavior: Human Brain Development and Developmental Disorders - Developmental disorders of speech and language
Progress in Brain Research, 2020Co-Authors: Kate E WatkinsAbstract:Abstract Functional and structural brain imaging studies of developmental disorders provide insights into their neural correlates and have potential to bridge the gap between genotype and phenotype. We have used such techniques to investigate the neural correlates of two developmental disorders of speech and language, in which a genetic etiology is either known or strongly suspected. The first disorder is one shared by the affected members of the KE Family who have a mutation in the FOXP2 gene. The brain structural and functional correlates of this disorder help clarify the nature of the behavioral impairment. They confirm that a deficit in auditory–motor learning of articulation patterns is core to the behavioral phenotype. In the second disorder, developmental stuttering, brain imaging data reveal functional abnormalities consistent with theories that it is caused by a basal ganglia deficit and structural differences consistent with an impairment in auditory–motor integration necessary for fluent speech. The common finding of basal ganglia abnormality in two developmental disorders of speech and language is discussed.
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Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia
Human Brain Mapping, 2003Co-Authors: Emma Belton, Faraneh Vargha-khadem, Kate E Watkins, C. H. Salmond, D G GadianAbstract:The KE Family is a large three-generational pedigree in which half of the members suffer from a verbal and orofacial dyspraxia in association with a point mutation in the FOXP2 gene. This report extends previous voxel-based morphometric analyses of magnetic resonance imaging (MRI) scans (Watkins et al. [2002] Brain 125:465-478) using a bilateral conjunction analysis. This searches specifically for areas of grey matter density that differ bilaterally in the affected members compared with both matched controls and the unaffected Family members. 3-D T1-weighted MRI datasets of 17 Family members (10 affected, 7 unaffected) and matched controls were compared. The most significant findings were reduced grey matter density bilaterally in the caudate nucleus, the cerebellum, and the left and right inferior frontal gyrus in the affected members. In addition, increased grey matter density was found bilaterally in the planum temporale. These results confirm that a point mutation in FOXP2 is associated with several bilateral grey matter abnormalities in both motor and language related regions. The results also demonstrate the advantages of using a conjunction analysis when bilateral abnormalities are suspected.
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mri analysis of an inherited speech and language disorder structural brain abnormalities
Brain, 2002Co-Authors: Kate E Watkins, F Varghakhadem, Alan Connelly, John Ashburner, R E Passingham, Karl J Friston, R S J Frackowiak, M Mishkin, D G GadianAbstract:Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large Family, known as the KE Family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE Family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected Family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected Family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected Family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE Family.
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Behavioural analysis of an inherited speech and language disorder: Comparison with acquired aphasia
Brain, 2002Co-Authors: Kate E Watkins, N. F. Dronkers, Faraneh Vargha-khademAbstract:Genetic speech and language disorders provide the opportunity to investigate the biological bases of language and its development. Critical to these investigations are the definition of behavioural phenotypes and an understanding of their interaction with epigenetic factors. Here, we report our investigations of the KE Family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The cognitive manifestations of this disorder were investigated using a number of linguistic and non-linguistic tests. The aims of these investigations were to establish the existence of a 'core' deficit, or behavioural phenotype, and to explain how such a deficit during development might give rise to the range of other impairments demonstrated by affected Family members. The affected Family members were compared both with the unaffected members and with a group of adult patients with aphasia resulting from a stroKE. The score on a test of repetition of non-words with complex articulation patterns successfully discriminated the affected and unaffected Family members. The affected Family members and the patients with aphasia had remarkably similar profiles of impairment on the tests administered. Premorbidly, however, the patients with aphasia had enjoyed a normal course of cognitive development and language experience. This benefit was reflected on a number of tests in which the patients with aphasia performed significantly better than the affected Family members and, in the case of some tests, at normal levels. We suggest that, in the affected Family members, the verbal and non-verbal deficits arise from a common impairment in the ability to sequence movement or in procedural learning. Alternatively, the articulation deficit, which itself might give rise to a host of other language deficits, is separate from a more general verbal and non-verbal developmental delay.
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Oral dyspraxia in inherited speech and language impairment and acquired dysphasia.
Brain and Language, 2000Co-Authors: Katherine J. Alcock, Kate E Watkins, Richard E. Passingham, Faraneh Vargha-khademAbstract:Half of the members of the KE Family suffer from an inherited verbal dyspraxia. The affected members of the Family have a lasting impairment in phonology and syntax. They were given various tests of oral praxis to investigate whether their deficit extends to nonverbal movements. Performance was compared to adult patients with acquired nonfluent dysphasia, those with comparable right-hemisphere lesions, and age-matched controls. Affected Family members and patients with nonfluent dysphasia were impaired overall at performing oral movements, particularly combinations of movements. It is concluded that affected members of the KE Family resemble patients with acquired dysphasia in having difficulties with oral praxis and that speech and language problems of affected Family members arise from a lower level disorder.
Anthony P Monaco - One of the best experts on this subject based on the ideXlab platform.
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identification of foxp2 truncation as a novel cause of developmental speech and language deficits
American Journal of Human Genetics, 2005Co-Authors: Kay D Macdermot, F Varghakhadem, Elena Bonora, Nuala Sykes, Anne Marie Coupe, Sonja C Vernes, Fiona Haslam Mckenzie, Robert L Smith, Anthony P Monaco, Simon E. FisherAbstract:FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE Family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE Family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.
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A forkhead-domain gene is mutated in a severe speech and language disorder
Nature, 2001Co-Authors: Simon E. Fisher, Faraneh Vargha-khadem, Jane A. Hurst, Anthony P MonacoAbstract:Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity^ 1 . Although studies of twins consistently indicate that a significant genetic component is involved^ 1 , 2 , 3 , most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait^ 4 . Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5 ). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval^ 6 . Here we show that the gene FOXP2 , which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE Family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.
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Localisation of a gene implicated in a severe speech and language disorder
Nature Genetics, 1998Co-Authors: Simon E. Fisher, Faraneh Vargha-khadem, Kate E Watkins, Anthony P Monaco, Marcus E. PembreyAbstract: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^1,2. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language^1, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis^2. 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^3. This Family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixa-tion rules^4–7, 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^8–10. In addition, affected members have a severe orofa-cial dyspraxia, and their speech is largely incomprehensible to the naive listener^10. 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 θ = 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.
F Varghakhadem - One of the best experts on this subject based on the ideXlab platform.
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2ps1 1 dissecting the neural networks involved in articulation through structural and functional brain imaging foxp2 and the KE Family
European Journal of Paediatric Neurology, 2011Co-Authors: Frederique Liegeois, Angela T Morgan, A Connolly, F VarghakhademAbstract:2PS1.1 Dissecting the neural networks involved in articulation through structural and functional brain imaging: FOXP2 and the KE Family F. Liegeois1, A.T. Morgan2, A. Connolly3, F. Vargha-Khadem1 *. 1Developmental Cognitive Neuroscience Unit, UCL Institute of Child Health, London, United Kingdom, 2Murdoch Childrens Research Institute, Melbourne, Australia, 3Brain Research Institute, Melbourne, Australia
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identification of foxp2 truncation as a novel cause of developmental speech and language deficits
American Journal of Human Genetics, 2005Co-Authors: Kay D Macdermot, F Varghakhadem, Elena Bonora, Nuala Sykes, Anne Marie Coupe, Sonja C Vernes, Fiona Haslam Mckenzie, Robert L Smith, Anthony P Monaco, Simon E. FisherAbstract:FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE Family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE Family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.
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mri analysis of an inherited speech and language disorder structural brain abnormalities
Brain, 2002Co-Authors: Kate E Watkins, F Varghakhadem, Alan Connelly, John Ashburner, R E Passingham, Karl J Friston, R S J Frackowiak, M Mishkin, D G GadianAbstract:Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large Family, known as the KE Family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE Family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected Family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected Family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected Family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE Family.