Genetic and environmental risks for specific language impairment in children

Specific language impairment (SLI) is the term used to refer to unexplained difficulties in language acquisition in children. Over the past decade, there has been rapid growth of evidence indicating that genes play an important part in the aetiology of SLI. However, further progress in elucidating the role of genes in causing SLI is limited by our lack of understanding of the phenotype. Studies to date have been hampered by the fact that we do not know whether SLI should be treated as a discrete disorder or a continuous variable, let alone which measures should be used to identify cases, or how many subtypes there are. Recent research suggests that theoretically motivated measures of underlying processes may be better than conventional clinical diagnoses for identifying aetiologically distinct types of language impairment. There has been a tendency for researchers to embrace parsimony and look for a single cause of SLI-or in any event, to identify different subtypes, each with a different single cause. Research is reviewed that suggests that may not be a fruitful approach to SLI, and that an approach in terms of multiple risk and protective factors, which is widely adopted in medicine, is more realistic.     

Genetic advances in the study of speech and language disorders

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.     

Association of specific language impairment (SLI) to the region of 7q31

FOXP2 (forkhead box P2) was the first gene characterized in which a mutation affects human speech and language abilities. A common developmental language disorder, specific language impairment (SLI), affects 6%-7% of children with normal nonverbal intelligence and has evidence of a genetic basis in familial and twin studies. FOXP2 is located on chromosome 7q31, and studies of other disorders with speech and language impairment, including autism, have found linkage to this region. In the present study, samples from children with SLI and their family members were used to study linkage and association of SLI to markers within and around FOXP2, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of FOXP2. No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the CFTR gene and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2.     

Defining language impairments in a subgroup of children with autism spectrum disorder

Autism spectrum disorder(ASD) is diagnosed on the basis of core impairments in pragmatic language skills, which are found across all ages and subtypes. In contrast, there is significant heterogeneity in language phenotypes, ranging from nonverbal to superior linguistic abilities, as defined on standardized tests of vocabulary and grammatical knowledge. The majority of children are verbal but impaired in language, relative to age-matched peers. One hypothesis is that this subgroup has ASD and co-morbid specific language impairment(SLI). An experiment was conducted comparing children with ASD to children with SLI and typically developing controls on aspects of language processing that have been shown to be impaired in children with SLI: repetition of nonsense words. Patterns of performance among the children with ASD and language impairment were similar to those with SLI, and contrasted with the children with ASD and no language impairment and typical controls, providing further evidence for the hypothesis that a subgroup of children with ASD has co-morbid SLI. The findings are discussed in the context of brain imaging studies that have explored the neural bases of language impairment in ASD and SLI, and overlap in the genes associated with elevated risk for these disorders.     

Genetic and phenotypic effects of phonological short-term memory and grammatical morphology in specific language impairment

Deficits in phonological short-term memory and aspects of verb grammar morphology have been proposed as phenotypic markers of specific language impairment (SLI) with the suggestion that these traits are likely to be under different genetic influences. This investigation in 300 first-degree relatives of 93 probands with SLI examined familial aggregation and genetic linkage of two measures thought to index these two traits, non-word repetition and tense marking. In particular, the involvement of chromosomes 16q and 19q was examined as previous studies found these two regions to be related to SLI. Results showed a strong association between relatives' and probands' scores on non-word repetition. In contrast, no association was found for tense marking when examined as a continuous measure. However, significant familial aggregation was found when tense marking was treated as a binary measure with a cut-off point of −1.5 SD, suggestive of the possibility that qualitative distinctions in the trait may be familial while quantitative variability may be more a consequence of non-familial factors. Linkage analyses supported previous findings of the SLI Consortium of linkage to chromosome 16q for phonological short-term memory and to chromosome 19q for expressive language. In addition, we report new findings that relate to the past tense phenotype. For the continuous measure, linkage was found on both chromosomes, but evidence was stronger on chromosome 19. For the binary measure, linkage was observed on chromosome 19 but not on chromosome 16.     

Familial loading in specific language impairment: patterns of differences across proband characteristics, gender and relative type

There is now little doubt that both environmental factors and genes are likely to make important contributions to the aetiology of specific language impairment (SLI). The most commonly proposed model for understanding these influences is the multifactorial model. In the present study we examine two expectations based on this model: that there will be a systematic relationship between the severity of proband language scores and the rate and severity of SLI in relatives and that relatives will be more strongly affected if they are relatives of a proband of the more rarely affected gender (female) because the latter require a higher genetic liability to become equally impaired. Ninety-three probands and their 300 first-degree relatives participated in this study. Results showed a relationship between proband severity at age 14 and an increased rate of SLI in relatives. This relationship was strong for child siblings and was significant with respect to both rate of SLI and severity over a range of language and literacy measures. In contrast, higher levels of SLI among relatives of female rather than male probands was entirely disproved.     

Putative miRNAs for the diagnosis of dyslexia,dyspraxia, and specific language impairment

Disorders of human communication abilities can be classified into speech and language disorders. Speech disorders (e.g., dyspraxia) affect the sound generation and sequencing, while language disorders (e.g., dyslexia and specific language impairment, or SLI) are deficits in the encoding and decoding of language according to its rules (reading, spelling, grammar). The diagnosis of such disorders is often complicated, especially when a patient presents more than one disorder at the same time. The present review focuses on these challenges. We have combined data available from the literature with an in silico approach in an attempt to identify putative miRNAs that may have a key role in dyspraxia, dyslexia and SLI. We suggest the use of new miRNAs, which could have an important impact on the three diseases. Further, we relate those miRNAs to the axon guidance pathway and discuss possible interactions and the role of likely deregulated proteins. In addition, we describe potential differences in expressional deregulation and its role in the improvement of diagnosis. We encourage experimental investigations to test the data obtained in silico.     

Memory and Language in Middle Childhood in Individuals with a History of Specific Language Impairment

This study reports on the sensitivity of sentence repetition as a marker of specific language impairment (SLI) in different subgroups of children in middle childhood and examines the role of memory and grammatical knowledge in the performance of children with and without language difficulties on this task. Eleven year old children, 197 with a history of SLI and 75 typically developing (TD) peers were administered sentence repetition, phonological short term memory (PSTM) and grammatical morphology tasks. Children with a history of SLI were divided into four subgroups: specific language impairment, non-specific language impairment, low cognition with resolved language and resolved. Performance on the sentence repetition task was significantly impaired in all four subgroups of children with a history of SLI when compared to their age peers. Regression analyses revealed grammatical knowledge was predictive of performance for TD children and children with a history of SLI. However, memory abilities were significantly predictive of sentence repetition task performance for children with a history of SLI only. Processes involved in sentence repetition are more taxing of PSTM for individuals with a history of SLI in middle childhood in a way that does not appear to be the case for TD children.     

Problems with tense marking in children with specific language impairment: not how but when

Many children with specific language impairment (SLI) have persisting problems in the correct use of verb tense, but there has been disagreement as to the underlying reason. When we take into account studies using receptive as well as expressive language tasks, the data suggest that the difficulty for children with SLI is in knowing when to inflect verbs for tense, rather than how to do so. This is perhaps not surprising when we consider that tense does not have a transparent semantic interpretation, but depends on complex relationships between inflections and hierarchically organized clauses. An explanation in terms of syntactic limitations contrasts with a popular morpho-phonological account, the Words and Rules model. This model, which attributes problems to difficulties with applying a rule to generate regular inflected forms, has been widely applied to adult-acquired disorders. There are striking similarities in the pattern of errors in adults with anterior aphasia and children with SLI, suggesting that impairments in appreciation of when to mark tense may apply to acquired as well as developmental disorders.     

Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits

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.     

A major susceptibility locus for specific language impairment is located on 13q21

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.     

Association of D16S515 microsatellite with specific language impairment on Robinson Crusoe Island, an isolated Chilean population: a possible key to understanding language development

Specific language impairment (SLI) is a developmental language disorder that occurs for no known reason. The disorder affects 2-8% of children. Some scientific evidence suggests that genetic factors are implicated in the etiology of SLI. The disorder is genetically complex. Two novel loci, SLI1 on chromosome 16q24 (MIM 606711) and SLI2 on chromosome 19q13 (MIM 606712), have been found to be highly correlated with SLI. Four genes have been identified as susceptibility genes. SLI occurs at an unusually elevated incidence (35%) among the population of Robinson Crusoe Island (Chile), which also has a high consanguinity rate. This finding supports the influence of genetic mechanisms in the transmission of SLI based on a founder effect. To investigate further the genetic involvement in this population, we collected blood samples from 115 islanders from 13 families with a language-impaired proband and from 18 families with a normal-language proband. The analysis of micro satellite marker D16S515, located in locus SLI1, demonstrated that the 230-bp allele was correlated with SLI and that the 232-bp allele was correlated with normal language development. The domain containing the D16S515 marker, therefore, may play a role in language development.     

Cost and complexity: selection for speech and language

The handicap principle has been applied to a number of different traits in the last three decades, but it is difficult to characterize its record, or even its perceived relevance, when it comes to an important human attribute—spoken language. In some cases, assumptions regarding the energetic cost of speech, and the veracity of linguistically encoded messages, have failed to recognize critical aspects of human development, cognition, and social ecology. In other cases, the fact that speech contains honest (physiological) information, and tends to be used honestly with family and friends, has been overlooked. Speech and language are functionally related but they involve different resources. Individuals can increase the attractiveness of their speech, and of more stylized vocal and verbal performances, without enhancing linguistic structure or content; and they can modify their use of language without significant changes in the physical form of speech. That its production costs are normally low enables speech to be produced extravagantly in bids for status and mating relationships, and in evolution, may have allowed its content—linguistic knowledge and structure—to become complex.     

Use of special education services by children with orofacial clefts

BACKGROUND: Our objective was to evaluate the use of special education services by children with orofacial clefts (OFCs). METHODS: We linked the birth certificates of children born from 1982–2001 in five counties of metropolitan Atlanta to a population‐based birth defects surveillance system to identify children with OFCs, and to the special education files for the school years 1992–2004 to identify children who used special education services. The special education data contained exceptionalities and services rendered for each school year. Prevalence ratios (PRs) and 95% CIs were calculated. The data were stratified by race/ethnicity, maternal education, type of OFC, and the presence of associated major malformations. In addition, we assessed the age at which special education began and the amount of time spent receiving services. RESULTS: Of the 777 children with OFCs, 201 (26%) were in special education at least 1 year compared with 8% of the children who had no major birth defects, yielding a PR of 3.2 (95% CI: 2.9–3.6). The most common exceptionality or service for children with an OFC was speech and language services. Compared with children with no birth defects, children with an OFC were four times more likely to be in this exceptionality (PR 3.8; 95% CI: 3.3–4.3). After excluding children in speech and language services, children with OFCs were still more likely to use special education services (PR 2.4; 95% CI: 1.7–3.2). CONCLUSIONS: Children with OFCs used special education services more often than children without birth defects. This information can help in planning for future population needs. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Cognitive abilities and language comprehension in preschool children with perinatal brain lesion

Perinatal brain lesion is a risk factor for development, making parents of such children particularly worried about consequences it may have on the child's cognitive and language development. Although literature findings on the outcome of perinatal brain lesion are inconsistent, most of the studies have found a positive general outcome, but also subtle deficits that affect the child's academic success. Since language comprehension and cognitive abilities influence learning abilities at school, we wanted to know how six-year olds who were selected based on pathological ultrasonographical findings (ischemic or hemorrhagic brain lesion) would perform on subtests of Wechsler battery (WISC) and language comprehension measures (Reynell Developmental Language Scale and Peabody Picture Vocabulary Test), compared with controls. The second issue we investigated was whether in children who suffered a perinatal brain lesion cognitive abilities predicted the level of language comprehension in the same way as in children without perinatal brain lesion. The relation between cognitive and linguistic abilities is still a controversial one, and a different relation would mean that these two groups of children have different structure of abilities probably due to perinatal brain lesion. Forty children who suffered a perinatal brain lesion and forty age-matched children without perinatal risk factors were examined. Our results showed that the groups differed more in linguistic than in cognitive variables. Also, the two groups showed different relation patterns between cognitive abilities and language comprehension. Cognitive abilities were statistically significantly associated with language comprehension in children who suffered a perinatal brain lesion, while this association was not statistically significant within the control group. Since a number of participants with perinatal brain lesion had language difficulties, it is presumed that they rely on cognitive abilities in order to overcome and compensate for language shortcomings.     

Common Genetic Variants in FOXP2 Are Not Associated with Individual Differences in Language Development

Much of our current knowledge regarding the association of FOXP2 with speech and language development comes from singleton and small family studies where a small number of rare variants have been identified. However, neither genome-wide nor gene-specific studies have provided evidence that common polymorphisms in the gene contribute to individual differences in language development in the general population. One explanation for this inconsistency is that previous studies have been limited to relatively small samples of individuals with low language abilities, using low density gene coverage. The current study examined the association between common variants in FOXP2 and a quantitative measure of language ability in a population-based cohort of European decent (n = 812). No significant associations were found for a panel of 13 SNPs that covered the coding region of FOXP2 and extended into the promoter region. Power analyses indicated we should have been able to detect a QTL variance of 0.02 for an associated allele with MAF of 0.2 or greater with 80% power. This suggests that, if a common variant associated with language ability in this gene does exist, it is likely of small effect. Our findings lead us to conclude that while genetic variants in FOXP2 may be significant for rare forms of language impairment, they do not contribute appreciably to individual variation in the normal range as found in the general population.     

Neuropsychiatry and deletions of 18q; case report and diagnostic considerations

The 18q deletion syndrome can be caused by several terminal and interstitial deletions of which terminal deletions of the distal part of 18q are the most frequent and known as the DeCroughy syndrome. The neuropsychiatric phenotype is not well documented and includes disorganised and disinhibited behaviours as well as language difficulties. Non development of language seems to be specific for cases with a more proximally located interstitial deletions. In the present paper a 18-year-old severely mentally retarded male with an interstitial deletion of 18q is described (46.XY,del(18)(q12.1q22.1) who was referred for behavioural problems and neuropsychiatric evaluation. No categorical psychiatric diagnosis could be established. Given this and other reports, it is advocated to describe the psychopathological phenotype of 18q deletions in a dimensional way that will result in a clinical picture characterised mainly by symptoms from the motor and motivation domains. Treatment should include primarily behavioural measures, combined if necessary with symptomatic psychopharmacotherapy.     

Assumptions and Properties of Limiting Pathway Models for Analysis of Epistasis in Complex Traits

For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the “missing heritability”. One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data (‘phantom heritability’) may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance.     

CMIP and ATP2C2 Modulate Phonological Short-Term Memory in Language Impairment

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 × 10⁻⁷ at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 × 10⁻⁵ at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.