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Background: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition., Methods: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2 -only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German., Results: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition., Conclusions: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chromosomal 7q31 deletions have been described in individuals with variable neurodevelopmental phenotypes including speech and language impairment. These copy number variants usually encompass FOXP2, haploinsufficiency of which represents a widely acknowledged cause for specific speech and language disorders. By chromosomal microarray analysis we identified a 4.7 Mb microdeletion at 7q31.2q31.31 downstream of FOXP2 in three family members presenting with variable speech, language and neurodevelopmental phenotypes. The index individual showed delayed speech development with impaired speech production, reduced language comprehension, and additionally learning difficulties, microcephaly, and attention deficit. His younger sister had delayed speech development with impaired speech production and partially reduced language comprehension. Their mother had attended a school for children with speech and language deficiencies and presented with impaired articulation. The deletion had occurred de novo in the mother, includes 15 protein-coding genes and is located in close proximity to the 3' end of FOXP2. Though a novel locus at 7q31.2q31.31 associated with mild neurodevelopmental and more prominent speech and language impairment is possible, the close phenotypic overlap with FOXP2-associated speech and language disorder rather suggests a positional effect on FOXP2 expression and function., (© 2020 Wiley Periodicals LLC.)

Purpose Speech and language disorders are hallmark features of 22q11.2 deletion syndrome (22qDS). Learning disabilities, cognitive deficits, palate abnormalities, velopharyngeal dysfunction, behavioral differences, and various medical and psychiatric conditions are also major features of this syndrome. The goal of this document is to summarize the state of the art of current clinical and scientific knowledge regarding 22qDS for speech-language pathologists (SLPs) and provide recommendations for clinical management. Method Best practices for management of individuals with 22qDS were developed by consensus of an expert international group of SLPs and researchers with expertise in 22qDS. These care recommendations are based on the authors' research, clinical experience, and literature review. Results This document describes the features of 22qDS as well as evaluation procedures, treatment protocols, and associated management recommendations for SLPs for the often complex communication disorders present in this population. Conclusion Early diagnosis and appropriate management of speech-language disorders in 22qDS is essential to optimize outcomes and to minimize the long-term effects of communication impairments. Knowledge of this diagnosis also allows anticipatory care and guidance regarding associated features for families, health care, and educational professionals.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Background: Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum., Methods: Chromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2 were performed in individuals with variable developmental disorders, and speech and language deficits., Results: We identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2 in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7 years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals., Conclusions: By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits., Competing Interests: The authors declare that they have no conflict of interest.

Language is a characteristic feature of human communication. Several familial language impairments have been identified, and candidate genes for language impairments already isolated. Studies comparing expression patterns of these genes in human brain are necessary to further understanding of these genes. However, it is difficult to examine gene expression in human brain. In this study, we used a non-human primate (common marmoset; Callithrix jacchus) as a biological model of the human brain to investigate expression patterns of human speech- and reading-related genes. Expression patterns of speech disorder- (FoxP2, FoxP1, CNTNAP2, and CMIP) and dyslexia- (ROBO1, DCDC2, and KIAA0319) related genes were analyzed. We found the genes displayed overlapping expression patterns in the ocular, auditory, and motor systems. Our results enhance understanding of the molecular mechanisms underlying language impairments., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Language disorders cover a wide range of conditions with heterologous and overlapping phenotypes and complex etiologies harboring both genetic and environmental influences. Genetic approaches including the identification of genes linked to speech and language phenotypes and the characterization of normal and aberrant functions of these genes have, in recent years, unraveled complex details of molecular and cognitive mechanisms and provided valuable insight into the biological foundations of language. Consistent with this approach, we have reviewed the functional aspects of allelic variants of genes which are currently known to be either causally associated with disorders of speech and language or impact upon the spectrum of normal language ability. We have also reviewed candidate genes associated with heritable speech and language disorders. In addition, we have evaluated language phenotypes and associated genetic components in developmental syndromes that, together with a spectrum of altered language abilities, manifest various phenotypes and offer details of multifactorial determinants of language function. Data from this review have revealed a predominance of regulatory networks involved in the control of differentiation and functioning of neurons, neuronal tracks and connections among brain structures associated with both cognitive and language faculties. Our findings, furthermore, have highlighted several multifactorial determinants in overlapping speech and language phenotypes. Collectively this analysis has revealed an interconnected developmental network and a close association of the language faculty with cognitive functions, a finding that has the potential to provide insight into linguistic hypotheses defining in particular, the contribution of genetic elements to and the modular nature of the language faculty.

The purpose of this study was to evaluate a global deficit in sequential processing as candidate endophenotypein a family with familial childhood apraxia of speech (CAS). Of 10 adults and 13 children in a three-generational family with speech sound disorder (SSD) consistent with CAS, 3 adults and 6 children had past or present SSD diagnoses. Two preschoolers with unremediated CAS showed a high number of sequencing errors during single-word production. Performance on tasks with high sequential processing loads differentiated between the affected and unaffected family members, whereas there were no group differences in tasks with low processing loads. Adults with a history of SSD produced more sequencing errors during nonword and multisyllabic real word imitation, compared to those without such a history. Results are consistent with a global deficit in sequential processing that influences speech development as well as cognitive and linguistic processing.

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

Foxp2(R552H) knock-in (KI) mice carrying a mutation related to human speech-language disorder exhibit impaired ultrasonic vocalization and poor Purkinje cell development. Foxp2 is a forkhead domain-containing transcriptional repressor that associates with its co-repressor CtBP; Foxp2(R552H) displays reduced DNA binding activity. A genetic connection between FOXP2 and CNTNAP2 has been demonstrated in vitro, but not in vivo. Here we show that Cntnap2 mRNA levels significantly increased in the cerebellum of Foxp2(R552H) KI pups, although the cerebellar population of Foxp2-positive Purkinje cells was very small. Furthermore, Cntnap2 immunofluorescence did not decrease in the poorly developed Purkinje cells of Foxp2(R552H) KI pups, although synaptophysin immunofluorescence decreased. Cntnap2 and CtBP were ubiquitously expressed, while Foxp2 co-localized with CtBP only in Purkinje cells. Taken together, these observations suggest that Foxp2 may regulate ultrasonic vocalization by associating with CtBP in Purkinje cells; Cntnap2 may be a target of this co-repressor., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We report on a 10-year-old patient with childhood apraxia of speech (CAS) and mild dysmorphic features. Although multiple karyotypes were reported as normal, a bacterial artificial chromosome array comparative genomic hybridization revealed the presence of a de novo 14.8-Mb mosaic deletion of chromosome 7q31. The deleted region involved several genes, including FOXP2, which has been associated with CAS. Interestingly, the deletion reported here was observed in about 50% of cells, which is the first case of mosaicism in a 7q31 deletion. Despite the presence of the deletion in only 50% of cells, the phenotype of the patient was not milder than other published cases. To date, 6 cases with a deletion of 9.1-20 Mb involving the FOXP2 gene have been reported, suggesting a new contiguous gene deletion syndrome characterized mainly by CAS caused by haploinsufficiency of the genes encompassed in the 7q critical region. This report suggests that children found with a deletion involving the FOXP2 region should be evaluated for CAS and that analysis of the FOXP2 gene including array comparative genomic hybridization should be considered in selected patients with CAS. Mosaic deletions in this area may also be considered as causative of CAS.

Vocal communication mediated by speech and language is a uniquely human trait, and has served an important evolutionary role in the development of our species. Deficits in speech and language functions can be of numerous types, including aphasia, stuttering, articulation disorders, verbal dyspraxia, and specific language impairment; language deficits are also related to dyslexia. Most communication disorders are prominent in children, where they are common. A number of these disorders have been shown to cluster in families, suggesting that genetic factors are involved, but their etiology at the molecular level is not well understood. In the past decade, genetic methods have proven to be powerful for understanding these etiologies. Linkage studies and molecular genetic analyses in a large family containing multiple individuals affected with verbal dyspraxia led to the discovery of mutations in the FOXP2 gene. This gene encodes a forkhead domain transcription factor, a finding that has led researchers to a new avenue of investigation into the substrates and mechanisms that underlie human speech development. In studies of stuttering, linkage and candidate gene approaches in consanguineous families identified mutations in the lysosomal enzyme-targeting pathway genes GNPTAB, GNPTG, and NAGPA, revealing a role for inherited defects in cell metabolism in this disorder. In specific language impairment, linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci. Although only a small fraction of all cases of speech and language disorders can be explained by genetic findings to date, the significant progress made thus far suggests that genetic approaches will continue to provide important avenues for research on this group of disorders.

Mental retardation affects 2-3% of the population and shows a high heritability.Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors.We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language., (©2010 Wiley-Liss, Inc.)

Developmental speech and language disorders cover a wide range of childhood conditions with overlapping but heterogeneous phenotypes and underlying etiologies. This characteristic heterogeneity hinders accurate diagnosis, can complicate treatment strategies, and causes difficulties in the identification of causal factors. Nonetheless, over the last decade, genetic variants have been identified that may predispose certain individuals to different aspects of speech and language difficulties. In this review, we summarize advances in the genetic investigation of stuttering, speech-sound disorder (SSD), specific language impairment (SLI), and developmental verbal dyspraxia (DVD). We discuss how the identification and study of specific genes and pathways, including FOXP2, CNTNAP2, ATP2C2, CMIP, and lysosomal enzymes, may advance our understanding of the etiology of speech and language disorders and enable us to better understand the relationships between the different forms of impairment across the spectrum., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Quantitative behavioral genetic studies have made it clear that communication disorders such as reading disability, language impairment, and autism spectrum disorders follow some basic principles: (1) complex disorders have complex causes, in which each clinical disorder is influenced by a number of separate genes; and (2) at least some behaviorally related disorders are influenced by the same genes. Recent advances in molecular and statistical methods have confirmed these principles and are now leading to an understanding of the genes that may be involved in these disorders and how their disruption may affect the development of the brain. The prospect is that the genes involved in these disorders will define a network of interacting neurologic functions and that perturbations of different elements of this network will produce susceptibilities for different disorders. Such knowledge would clarify the underlying deficits in these disorders and could lead to revised diagnostic conceptions. However, these goals are still in the future. Identifying the individual genes in such a network is painstaking, and there have been seemingly contradictory studies along the way. Improvements in study design and additional functional analysis of genes are gradually clarifying many of these issues. When combined with careful phenotypic studies, molecular genetic studies have the potential to refine the clinical definitions of communication disorders and influence their remediation.

Foxp subfamily genes were recently recognized to be members of the Fox gene family. Foxp subfamily members contain a zinc finger domain and a leucine zipper motif in addition to a forkhead domain and their DNA binding capacities and transcriptional activities are regulated by homo- and heterodimerization via a zinc finger and a leucine zipper motif. Three Foxp subfamily members are abundantly expressed in developing brains. The expression patterns of these genes are overlapping, but they are distinctly expressed in some regions. Thus these genes appear to be involved in the development control of the central nervous system. Recently, FOXP2, a member of the Foxp subfamily, was identified as the first gene to be linked to an inherited form of language and speech disorder. The discovery of a mutation in FOXP2 in a family with a speech and language disorder opened a new window to understanding the genetic cascades and neural circuits that underlie speech and language via molecular approaches. The spatiotemporal FOXP2 mRNA expression pattern suggests that the basic neural network that underlies speech and language may include motor-related circuits, including frontostriatal and/or frontocerebellar circuits. This assumption is supported by brain imaging data obtained by using fMRI and PET on the FOXP2-mutated patients and also by analysis of Foxp2 mutant mice.

Background: This article selectively reviews the status of the genetic research in the field of speech and language disorders., Methods: Major contributions to the field are selected, presented, and discussed., Results: The field presents itself through a variety of findings, characterized by both consistencies and inconsistencies., Conclusions: The last 30 + years of the field unequivocally testify to the importance of genetic factors in the acquisition of speech and language. However, the details of how these factors exert their influence are yet to be determined.

Heritability estimates for specific language impairment (SLI) have been inconsistent. Four twin studies reported heritability of 0.5 or more, but a recent report from the Twins Early Development Study found negligible genetic influence in 4-year-olds. We considered whether the method of ascertainment influenced results and found substantially higher heritability if SLI was defined in terms of referral to speech and language pathology services than if defined by language test scores. Further analysis showed that presence of speech difficulties played a major role in determining whether a child had contact with services. Childhood language disorders that are identified by population screening are likely to have a different phenotype and different etiology from clinically referred cases. Genetic studies are more likely to find high heritability if they focus on cases who have speech difficulties and who have been referred for intervention.

We previously discovered that mutations of the human FOXP2 gene cause a monogenic communication disorder, primarily characterized by difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech. Affected people have deficits in expressive and receptive linguistic processing and display structural and/or functional abnormalities in cortical and subcortical brain regions. FOXP2 provides a unique window into neural processes involved in speech and language. In particular, its role as a transcription factor gene offers powerful functional genomic routes for dissecting critical neurogenetic mechanisms. Here, we employ chromatin immunoprecipitation coupled with promoter microarrays (ChIP-chip) to successfully identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. We focus on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression in our cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, we demonstrate significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represents the first identification and in vivo verification of neural targets regulated by FOXP2. Our data indicate that FOXP2 has dual functionality, acting to either repress or activate gene expression at occupied promoters. The identified targets suggest roles in modulating synaptic plasticity, neurodevelopment, neurotransmission, and axon guidance and represent novel entry points into in vivo pathways that may be disturbed in speech and language disorders.

We report on a young male with moderate mental retardation, dysmorphic features, and language delay who is deleted for 7q31.1-7q31.31. His full karyotype is 46,XY,der(7)del(7)(q31.1q31.31)ins(10;7)(q24.3;q31.1q31.31)mat. This child had language impairment, including developmental verbal dyspraxia, but did not meet criteria for autism according to standardized ADOS testing. Our patient's deletion, which is the smallest reported deletion including FOXP2, adds to the body of evidence that supports the role of FOXP2 in speech and language impairment, but not in autism. A reported association between autism and deletions of WNT2, a gene also deleted in our patient, is likewise not supported by our case. Previously, fine mapping with microsatellites markers within in a large three-generation family, in which half the members had severe specific language impairment, aided the localization of the SPCH1 locus to 7q31 within markers D7S2459 (107.1 Mb) and D7S643 (120.5 Mb). Additionally, chromosome rearrangement of 7q31 and mutational analyses have supported the growing evidence that FOXP2, a gene within the SPCH1 region, is involved with speech and language development. It is unclear however whether the AUTS1 (autistic spectrum 1) locus, highly linked to 7q31, overlaps with the SPCH1 and FOXP2., (Copyright 2007 Wiley-Liss, Inc.)

Why do some children fail to acquire speech and language skills despite adequate environmental input and overtly normal neurological and anatomical development? It has been suspected for several decades, based on indirect evidence, that the human genome might hold some answers to this enigma. These suspicions have recently received dramatic confirmation with the discovery of specific genetic changes which appear sufficient to derail speech and language development. Indeed, researchers are already using information from genetic studies to aid early diagnosis and to shed light on the neural pathways that are perturbed in these inherited forms of speech and language disorder. Thus, we have entered an exciting era for dissecting the neural bases of human communication, one which takes genes and molecules as a starting point. In the current article I explain how this recent paradigm shift has occurred and describe the new vistas that have opened up. I demonstrate ways of bridging the gaps between molecules, neurons and the brain, which will provide a new understanding of the aetiology of speech and language impairments., (Copyright 2007 S. Karger AG, Basel.)

Purpose: This study examined (a) the extent of genetic and environmental influences on children's articulation and language difficulties and (b) the phenotypic associations between such difficulties and direct assessments of reading-related skills during early school-age years., Method: Behavioral genetic analyses focused on parent-report data regarding the speech-language skills of 248 twin pairs (M = 6.08 years) from the Western Reserve Reading Project. In addition, phenotypic associations between children's speech-language status and direct assessments of early reading-related abilities were examined through hierarchical linear modeling (HLM)., Results: Probandwise concordance rates and intraclass tetrachoric correlations indicated high heritability for children's difficulties in expressive language and articulation, with estimates of .54 and .97 accordingly. HLM results indicated that children with histories of speech-language difficulties scored significantly lower than unaffected children on various measures of early reading-related abilities., Conclusions: Results from the parent-report survey provided converging evidence of genetic effects on children's speech and language difficulties and suggest that children with a history of speech-language difficulties are at risk for lower performance on early reading-related measures. The extent of risk differed across measures and appeared greatest for children who demonstrated a history of difficulties across articulation, expressive language, and receptive language. Implications for future genetic research and clinical practice are discussed.

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.

Objective: Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior., Methods: Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features., Results: Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization., Conclusions: Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.

Unlabelled: Wolf-Hirschhorn syndrome (WHS), a condition resulting from a distal deletion of the short arm of chromosome 4, is usually associated with a severe phenotypic expression including multiple malformations, delayed psychomotor development, and profound learning disabilities. As far as communicative development is concerned, speech is usually absent and comprehension is limited to simple orders or to a specific context. There is some suggestion, however, that the developmental outcome in WHS depends on deletion size. This paper reports on an individual with WHS illustrating that a smaller deletion may result in a milder phenotype with respect to communicative abilities. This 10-year-old girl developed speech and language to a considerable degree. Although most children with this syndrome are severely limited in communicative abilities, the school-based speech-language pathologist working with a special education caseload may encounter WHS children with smaller deletions (and thus less severe phenotypes) who may profit from speech language pathology services., Learning Outcomes: The reader will learn about the genetics, incidence, and clinical characteristics of Wolf-Hirschhorn syndrome, and about the communicative abilities and genotype/phenotype correlations in children with this syndrome.

Disruption of FOXP2, a gene encoding a forkhead-domain transcription factor, causes a severe developmental disorder of verbal communication, involving profound articulation deficits, accompanied by linguistic and grammatical impairments. Investigation of the neural basis of this disorder has been limited previously to neuroimaging of affected children and adults. The discovery of the gene responsible, FOXP2, offers a unique opportunity to explore the relevant neural mechanisms from a molecular perspective. In the present study, we have determined the detailed spatial and temporal expression pattern of FOXP2 mRNA in the developing brain of mouse and human. We find expression in several structures including the cortical plate, basal ganglia, thalamus, inferior olives and cerebellum. These data support a role for FOXP2 in the development of corticostriatal and olivocerebellar circuits involved in motor control. We find intriguing concordance between regions of early expression and later sites of pathology suggested by neuroimaging. Moreover, the homologous pattern of FOXP2/Foxp2 expression in human and mouse argues for a role for this gene in development of motor-related circuits throughout mammalian species. Overall, this study provides support for the hypothesis that impairments in sequencing of movement and procedural learning might be central to the FOXP2-related speech and language disorder.

A significant number of individuals have unexplained difficulties with acquiring normal speech and language, despite adequate intelligence and environmental stimulation. Although developmental disorders of speech and language are heritable, the genetic basis is likely to involve several, possibly many, different risk factors. Investigations of a unique three-generation family showing monogenic inheritance of speech and language deficits led to the isolation of the first such gene on chromosome 7, which encodes a transcription factor known as FOXP2. Disruption of this gene causes a rare severe speech and language disorder but does not appear to be involved in more common forms of language impairment. Recent genome-wide scans have identified at least four chromosomal regions that may harbor genes influencing the latter, on chromosomes 2, 13, 16, and 19. The molecular genetic approach has potential for dissecting neurological pathways underlying speech and language disorders, but such investigations are only just beginning.

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. Although studies of twins consistently indicate that a significant genetic component is involved, 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. 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. 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.

Data from two twin studies were used to address two related questions. First, is there any association between handedness and specific speech and language impairment (SSLI) in children? Second, is there genetic influence on individual differences in handedness and, if so, are the same genes implicated in the cause of SSLI? The first study used data from 58 MZ and 26 DZ pairs previously recruited for an investigation into the genetic origins of SSLI. All pairs contained at least one child with SSLI. Handedness was assessed using a preference inventory and a tapping task from which a laterality quotient (LQ) was derived. There were no handedness differences between these twins and 172 singleborn controls, and neither measure revealed any association between handedness and SSLI. The data were equally well-fitted by a CE model (no genetic influence) and an AE model (no effect of shared environment) for both hand preference and tapping LQ. Nonshared environment was the largest influence on handedness for both measures. Bivariate analysis indicated no overlapping genetic influences on SSLI and handedness. In the second study, handedness was assessed in a general population sample of 48 MZ and 44 DZ twin pairs, aged 7 to 13 years, using a preference inventory and a peg-moving task. A subset of children was also given a test that assessed persistence of hand preference when reaching across the midline. The latter was the only measure to relate to children's language status, with language-impaired children showing less midline crossing. This appears to reflect neurodevelopmental immaturity, rather than a stable trait. To investigate familial transmission of handedness, inventory data for parents and their twins were combined for both samples. The most parsimonious model was one that accounted for parent-child resemblance solely in terms of cultural transmission. Overall, there was no evidence that genes play a role in determining stable individual differences in hand preference. Insofar as there are links between handedness and speech and language difficulties, these reflect delayed neuromotor maturation.

Purpose: The purpose of this investigation is to describe the communication profile of children with the 22q11.2 deletion syndrome from infancy through school age and to examine the influence of other medical aspects, such as palate anomalies, learning disorders, and cardiac defects of the syndrome to communication., Methods: Seventy-nine children were examined using standardized tests of speech and language and perceptual measures of resonance and voice., Results: Results show significant delay in emergence of speech and language milestones with delay/disorder in speech-language processes persisting into the school aged years, including those children diagnosed with nonverbal learning disabilities. Persistent articulation and resonance disorders were also present, presumed to be related in part to palatal anomalies. No correlation was found between cardiac status, learning disorders, palate anomalies and communication disorders., Conclusion: The need for early identification and management of communication skills is crucial in the care of children with the 22q11.2 deletion.

We estimate the prevalence of speech delay (L.D. Shriberg, D. Austin, B. A. Lewis, J. L. McSweeny, & D. L. Wilson, 1997b) in the United States on the basis of findings from a demographically representative population subsample of 1,328 monolingual English-speaking 6-year-old children. All children's speech and language had been previously assessed in the "Epidemiology of Specific Language Impairment" project (see J. B. Tomblin et al., 1997), which screened 7,218 children in stratified cluster samples within 3 population centers in the upper Midwest. To assess articulation, the Word Articulation subtest of the Test of Language Development-2: Primary (Newcomer & Hammill, 1988) was administered to each of the 1,328 children, and conversational speech samples were obtained for a subsample of 303 (23%) children. The 6 primary findings are as follows: (a) The prevalence of speech delay in 6-year-old children was 3.8%; (b) speech delay was approximately 1.5 times more prevalent in boys (4.5%) than girls (3.1%); (c) cross-tabulations by sex, residential strata, and racial/cultural backgrounds yielded prevalence rates for speech delay ranging from 0% to approximately 9%; (d) comorbidity of speech delay and language impairment was 1.3%, 0.51% with Specific Language Impairment (SLI); (e) approximately 11-15% of children with persisting speech delay had SLI; and (f) approximately 5-8% of children with persisting SLI had speech delay. Discussion includes implications of findings for speech-language phenotyping in genetics studies.

This paper is part of a study of prosodic features of familial language impairment (FLI) in English. It reports the results of a set of experiments designed to investigate the factors that play a role in the assignment of stress to words which are longer than two syllables. It appears that stress assignment in FLI is constrained by a restriction limiting the maximal size of the stress domain to a bisyllabic unit, formally defined as the minimal prosodic word. We hypothesize that this restriction is responsible for variable patterns of word truncation, stress levelling and compounding that characterize the production of polysyllabic words.

Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.

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.

Language impairments have been hypothesized to have a genetic component. Previous studies of the familial aggregation of language impairments have relied on a retrospective approach based on parental/self-reported history of language development. This study examined familial aggregation prospectively, by investigating language acquisition and cognitive development in the younger siblings and offspring of individuals with well-defined language impairments. It was predicted that children with a positive family history for language impairments would be more likely to show delays in language acquisition than would age- and gender-matched controls. Similar delays were not expected in nonlinguistic domains, such as conceptual, gestural, or general cognitive development. Ten children with a positive family history and 10 age- and gender-matched controls were tested. Analyses of linguistic and cognitive assessments at 16 to 26 months confirmed the predictions. Children with a family history of language impairments had lower receptive and expressive language scores than controls, with 50% of them scoring at least 1.5 SD below the mean for their age. At the same time, performance on a number of tasks that did not rely on language abilities did not differ as a function of family history. These results indicate that children with a positive family history for language impairments are at risk for language delay; the results also support a familial component to language impairments.

The aim of this work was to study the frequency of speech disorders in Israeli Arab children and its association with parental consanguinity. A questionnaire was sent to the parents of 1,495 Arab children attending kindergarten and the first two grades of the seven primary schools in the town of Taibe. Eight-six percent (1,282 parents) responded. The answers to the questionnaire revealed that 25% of the children reportedly had a speech and language disorder. Of the children identified by their parents as having a speech disorder, 44 were selected randomly for examination by a speech specialist. The disorders noted in this subgroup included errors in articulation (48.0%), poor language (18%), poor voice quality (15.9%); stuttering (13.6%), and other problems (4.5%). Rates of affected children of consanguineous and non-consanguineous marriages were 31% and 22.4%, respectively (p < 0.01). We conclude that speech disorders are an important problem among Israeli Arab schoolchildren. More comprehensive programs are needed to facilitate diagnosis and treatment.

Familial aggregation of speech and language disorders was examined as a basis of subgrouping children with phonologic disorders. Fifty-nine children with phonologic disorders were subgrouped according to whether or not other nuclear family members reported a history of speech/language disorders. Thirty-four subjects (58%) reported at least one other nuclear family member affected and 25 subjects (42%) reported no other nuclear family members affected. Groups were compared on measures of articulation, phonology, language, and oral motor skills to determine if the familial phonologic subgroup presented a unique profile of speech and language deficits. Significant group differences were not observed. However, children with positive nuclear family histories tended to perform more poorly than children without histories on all tasks, although not reaching significance. Although all parents were considered to have achieved normal adult articulation, parents of children with positive family histories also tended to perform more poorly than parents of children with negative histories. Results suggested that poorer oral motor coordination and productive phonology may distinguish individuals with familial phonologic disorders from individuals with phonologic disorders of unknown origin.

Speech/language disorders are common in the fragile X syndrome. [Howard-Peebles, 1979: Am J Hom Genet 31:214-222; Renier et al., 1983: J Ment Defic Res 27:51-59; Sparks, 1984: Birth Defects and Speech-Language Disorders, pp. 39-43; Hanson et al., 1986: Am J Med Genet 23:195-206]. Verbal paraphasias have been considered a rare feature and word-finding difficulties have seldom been reported. Here we report on ten Brazilian patients who were evaluated for speech/language disturbances and found that word-finding difficulties were present in 50% of the cases, which is a slightly higher frequency than that of clear dyspraxia. We suggest, therefore, that word-finding difficulties and verbal dyspraxia can be a common feature within the spectrum of this syndrome. Additional speech findings are discussed.

A pronounced speech and language disorder affecting half of the 30 members of the four-generational KE family has been attributed by some researchers to a specific defect in the generation of morphosyntactic rules. The reported selectivity of the impairment has led to the view that the affected members suffer from a grammar-specific disorder. Our investigations of the same KE family indicate that the inherited disorder has a broad phenotype which transcends impaired generation of syntactical rules and includes a striking articulatory impairment as well as defects in intellectual, linguistic, and orofacial praxic functions generally. Although the evidence from this family thus provides no support for the existence of "grammar genes," their linguistic difficulties do constitute a prominent part of their phenotype. Investigations of the neural and genetic correlates of their disorder could therefore uncover important clues to some of the bases of the primary human faculties of speech and language.

We assessed levels of communication disturbance by counting the frequency of unclear linguistic references in the speech of 10 stable schizophrenic outpatients, 18 of their "unaffected" parents, and 10 nonpsychiatric controls, in affectively negative versus affectively positive conditions. Patient and parent groups scored approximately equally on the reference performance measure in the positive condition, and significantly more poorly than controls. Patients' speech deteriorated significantly in the negative condition, while parents' and controls' speech did not. The degree to which patients' speech was reactive to negative affect corresponded to the severity of their core positive symptoms of delusions and hallucinations. Poor reference performance in parents predicted poor performance and a more severe history of positive symptoms in their patient offspring. These data support the hypothesis that poor reference performance represents a vulnerability marker for schizophrenia, and that affective reactivity of language symptoms is associated with an underlying positive schizophrenic process.

Fifty-seven same-sex twin sets (32 monozygotic and 25 dizygotic) were examined for concordance of speech and language disorders. Results showed monozygotic twins to have higher concordance than dizygotic twins. In addition, monozygotic twins were more similar in the types of disorders they presented than dizygotic twins. Positive family histories for speech, language, and learning disorders were reported in the nuclear families of the twins.

As is typical in science, early work in an area is bound to have weaknesses. Therefore, it is not unexpected that the extent to which conclusions can be drawn from the current research on the genetics of DLD is limited. These limitations stem from the use of heterogeneous samples, the use of overly broad phenotypes, survey rather than objective test data, and only a few studies looking beyond simple familiarity. Future research is in progress that attempts to correct for these weaknesses. Still, some practically useful information can be gleaned from the work done thus far. First, we can now hypothesize something about the pathway from gene to DLD phenotype. Much of DLD, like RD, may be a manifestation of early genetic effects on the structural development of the brain (e.g., Plante, Swisher, and Vance, 1991; Plante, 1991; Molfese and Betz, 1988). However, consequences of these genetic effects for language development can still be modified by environmental events (e.g., treatment). Furthermore, genetic effects do not act in isolation and they are not necessarily static. A number of genetic and non-genetic events in the course of development may positively or negatively modify the disorder (e.g., Tomblin, 1989, Tallal et al., 1991; Molfese and Holcomb, 1989). A related point is that there is evidence for genetic heterogeneity in DLD. That different modes of transmission have been put forth by different authors, suggests that a variety of genetic forms of DLD may exist. This idea is further supported by noting that DLD is a common outcome of a number of clinical syndromes having very different genetic bases (e.g., Williams syndrome, Down syndrome, fragile X, etc.; Siegel-Sadewitz and Shprintzen, 1982; Bellugi et al., 1991). This does not rule out the possibility that a majority of nonsyndromic DLD is due to one or a few major genes, however. Finally, there is also evidence for behavioral heterogeneity in DLD. The data suggest that the genes for DLD are variably expressed. For example, in families selected through a DLD proband, a number of different language-related problems have been noted. Furthermore, when a globally defined DLD individual is examined closely, it is common to find a collection of symptoms, sometimes spanning all the major domains of language (Weiss and Lillywhite, 1981). Overall, the data and concepts presented in this article suggest that the clinician should take careful family histories of clients and, when doing so, attempt to ascertain the specific symptoms that family members other than the client exhibit.(ABSTRACT TRUNCATED AT 400 WORDS)

The purpose of this review is to provide speech-language pathologists and special educators with an awareness of genetics and specific syndromes that involve a speech, language, or hearing component. Both genetic and environmental etiologies are discussed. A description is provided for some of the physical anomalies associated with selected syndromes that also include speech and language deficits. These are presented to provide a rationale for the speech-language pathologist as well as special educators to become more active team members in the identification of syndromes, promote early remedial intervention, and increase interaction with other disciplines in dealing with the multihandicapped child.

This paper is a comprehensive review of known examples of genetically influenced learning disabilities (LDs) and speech and language disorders (SLDs). The review is divided between 2 broad classes of studies: (a) those which begin with an LD or SLD phenotype that appears to be familial and attempt to learn more about the specifics of genetic transmission, if any; and (b) those which begin with a group of individuals, all of whom share a given documented genetic risk factor, to see if it leads to a specific LD or SLD. Included in the first category are familial dyslexia, stuttering, and other speech and language disorders. In the second category are included sex chromosome anomalies, treated PKU, and minor autosomal anomalies. Issues of definition, variability, and developmental changes in the cognitive phenotype are discussed throughout. The implications of this work for our understanding of cognitive development and its bases in brain development and genetics are also discussed.

The present study examined the familial basis for severe phonological disorders. Twenty children with severe phonological disorders and their siblings were compared to 20 normally developing children and their siblings on measures of phonology, language, reading, and motor ability. Results revealed that the siblings of the disordered children performed more poorly than control siblings on phonology and reading measures. Disordered subjects' phonological skills correlated significantly and positively with their siblings', whereas controls' scores did not. Families of disordered children reported significantly more members with speech and language disorders and dyslexia than did families of controls. Sex differences were reflected in the incidence but not the severity or type of disorder present. These findings suggest a familial basis for at least some forms of severe phonological disorders.