Family history interview of a broad phenotype in specific language impairment and matched controls

The aim was to study a broader phenotype of language‐related diagnoses and problems in three generations of relatives of children with specific language impairment (SLI). Our study is based on a family history interview of the parents of 59 children with SLI and of 100 matched control children, exploring the prevalence of problems related to language, reading, attention, school achievement and social communication as well as diagnoses such as attention‐deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, dyslexia, mental retardation, cleft palate and stuttering. The results show a spectrum of language‐related problems in families of SLI children. In all three generations of SLI relatives, we found significantly higher prevalence rates of language, literacy and social communication problems. The risk of one or both parents having language‐related diagnoses or problems was approximately six times higher for the children with SLI (85%) than for the control children (13%) (odds ratio = 37.2). We did not find a significantly higher prevalence of the diagnoses ADHD, autism or Asperger syndrome in the relatives of the children with SLI. However, significantly more parents of the children with SLI had problems with attention/hyperactivity when compared with the parents of controls. Our findings suggest common underlying mechanisms for problems with language, literacy and social communication, and possibly also for attention/hyperactivity symptoms.     

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.     

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.     

Language,Reading, and Math Learning Profiles in an Epidemiological Sample of School Age Children

Dyscalculia, dyslexia, and specific language impairment (SLI) are relatively specific developmental learning disabilities in math, reading, and oral language, respectively, that occur in the context of average intellectual capacity and adequate environmental opportunities. Past research has been dominated by studies focused on single impairments despite the widespread recognition that overlapping and comorbid deficits are common. The present study took an epidemiological approach to study the learning profiles of a large school age sample in language, reading, and math. Both general learning profiles reflecting good or poor performance across measures and specific learning profiles involving either weak language, weak reading, weak math, or weak math and reading were observed. These latter four profiles characterized 70% of children with some evidence of a learning disability. Low scores in phonological short-term memory characterized clusters with a language-based weakness whereas low or variable phonological awareness was associated with the reading (but not language-based) weaknesses. The low math only group did not show these phonological deficits. These findings may suggest different etiologies for language-based deficits in language, reading, and math, reading-related impairments in reading and math, and isolated math disabilities.     

Distinct genetic influences on grammar and phonological short-term memory deficits: evidence from 6-year-old twins

Children with language impairments have limitations of phonological short-term memory (STM) and have distinctive problems with certain aspects of grammar. Both deficits have been proposed as phenotypic markers of heritable language impairment. We studied 173 twin pairs, selected to be over-representative of children with risk of developmental language impairment, using a battery of standardized language and intelligence tests, a test of nonword repetition to index phonological STM and two elicitation tasks to assess use of verb tense marking. As predicted, the phonological STM and the verb tense measures both discriminated children with risk of language impairment from low risk children, and DeFries-Fulker analysis showed that impairments on both tasks were significantly heritable. However, there was minimal phenotypic and etiological overlap between the two deficits, suggesting that different genes are implicated in causing these two kinds of language difficulty. From an evolutionary perspective, these data are consistent with the view that language is a complex function that depends on multiple underlying skills with distinct genetic origins.     

Word production errors in children with developmental language impairments

This review focuses on the errors that children with developmental language impairments make on three types of word production tasks: lexical retrieval, the elicitation of derivationally complex forms and the repetition of non-sense forms. The studies discussed in this review come principally from children with specific language impairment, and from children who are English-speakers or deaf users of British sign language. It is argued that models of word production need to be able to account for the data presented here, and need to have explanatory power across both modalities (i.e. speech and sign).     

Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are 1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).     

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.     

A locus for an auditory processing deficit and language impairment in an extended pedigree maps to 12p13.31‐q14.3

Despite the apparent robustness of language learning in humans, a large number of children still fail to develop appropriate language skills despite adequate means and opportunity. Most cases of language impairment have a complex etiology, with genetic and environmental influences. In contrast, we describe a three‐generation German family who present with an apparently simple segregation of language impairment. Investigations of the family indicate auditory processing difficulties as a core deficit. Affected members performed poorly on a nonword repetition task and present with communication impairments. The brain activation pattern for syllable duration as measured by event‐related brain potentials showed clear differences between affected family members and controls, with only affected members displaying a late discrimination negativity. In conjunction with psychoacoustic data showing deficiencies in auditory duration discrimination, the present results indicate increased processing demands in discriminating syllables of different duration. This, we argue, forms the cognitive basis of the observed language impairment in this family. Genome‐wide linkage analysis showed a haplotype in the central region of chromosome 12 which reaches the maximum possible logarithm of odds ratio (LOD) score and fully co‐segregates with the language impairment, consistent with an autosomal dominant, fully penetrant mode of inheritance. Whole genome analysis yielded no novel inherited copy number variants strengthening the case for a simple inheritance pattern. Several genes in this region of chromosome 12 which are potentially implicated in language impairment did not contain polymorphisms likely to be the causative mutation, which is as yet unknown.     

Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment

Specific language impairment is a neurodevelopmental disorder characterized by impairments essentially restricted to the domain of language and language learning skills. This contrasts with autism, which is a pervasive developmental disorder defined by multiple impairments in language, social reciprocity, narrow interests and/or repetitive behaviors. Genetic linkage studies and family data suggest that the two disorders may have genetic components in common. Two samples, from Canada and the US, selected for specific language impairment were genotyped at loci where such common genes are likely to reside. Significant evidence for linkage was previously observed at chromosome 13q21 in our Canadian sample (HLOD 3.56) and was confirmed in our US sample (HLOD 2.61). Using the posterior probability of linkage (PPL) to combine evidence for linkage across the two samples yielded a PPL over 92%. Two additional loci on chromosome 2 and 7 showed weak evidence for linkage. However, a marker in the cystic fibrosis transmembrane conductance regulator (7q31) showed evidence for association to SLI, confirming results from another group (O'Brien et al. 2003). Our results indicate that using samples selected for components of the autism phenotype may be a useful adjunct to autism genetics.     

Peanut allergy in relation to heredity,maternal diet,and other atopic diseases: results of a questionnaire survey,skin prick testing,and food challenges.

OBJECTIVES: To determine rates of other atopic manifestations in people with peanut allergy and the prevalence of such allergy in their families. DESIGN: A survey of people with self reported peanut allergy and people referred by their general practitioner for suspected peanut allergy; survey and skin testing of 50 children with reported peanut allergy and their available first degree relatives. SUBJECTS: 622 adults and children with reported, suspected, or known peanut allergy. MAIN OUTCOME MEASURES: Prevalence of peanut allergy and other allergies in the families of people with peanut allergy. RESULTS: 622 valid completed questionnaires were returned out of the 833 questionnaires dispatched (74.7%). All forms of atopy were both more common in successive generations (P < 0.0001) and more common in maternal than paternal relatives (P < 0.0001). Peanut allergy was reported by 0.1% (3/2409) of grandparents, 0.6% (7/1213) of aunts and uncles, 1.6% (19/1218) of parents, and 6.9% (42/610) of siblings. Consumption of peanuts while pregnant or breast feeding was more common among mothers of probands aged < or = 5 years than mothers of probands aged > 5 years (P < 0.001). Age of onset correlated inversely with year of birth (r = -0.6, P < 0.001). Skin prick testing of 50 children with reported peanut allergy and their families: 7 probands (14%) had a negative result for peanut. Peanut allergy was refuted by food challenge in all those tested (5/7). No parent and 13% (5/39) of siblings had a positive result on skin prick testing for peanut. Two of these siblings had negative challenge with peanuts. The prevalence of peanut allergy in siblings is therefore 3/39 (7%). CONCLUSIONS: Peanut allergy is more common in siblings of people with peanut allergy than in the parents or the general population. Its apparently increasing prevalence may reflect a general increase of atopy, which is inherited more commonly from the mother. Peanut allergy is presenting earlier in life, possibly reflecting increased consumption of peanut by pregnant and nursing mothers.     

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.     

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders

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.     

Velopharyngeal variations in relatives of cleft-affected individuals

Eighteen families each with two or more cleft lip and palate patients were studied by speech cephalometry for evidence of velopharyngeal inadequacy (VPI). With this total of 56 persons, three groups were recognized: 1) patients with cleft lip only (N = 7), 2) unaffected sibs of CL(P) probands and the unaffected parents with the positive clefting history on their side of the family (N = 33), and 3) unaffected parents with negative CL(P) history to their side of the family (N = 16). The latter served as controls. The velopharyngeal mechanism in function was evaluated by voicing the fricative/S/. The results showed no significant differences in the length of either the resting soft palate or pharyngeal depth among the three groups. Even though a significant (P less than 0.01) increase in soft palate length while voicing /S/ was found in group 2 relatives compared to group 3 controls, the failure to find differences in either resting palate length or pharyngeal depth coupled with a failure to demonstrate VPI in group 2 subjects by speech testing leaves the value of this observation uncertain.     

Type II diabetes of early onset: a distinct clinical and genetic syndrome?

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.     

Parental generalized EEG alpha activity predisposes to spike wave discharges in offspring

Familial and twin studies have shown that the individual variability of the normal human electroencephalogram (EEG) is largely genetically determined. In epileptology, these genetic parameters of the EEG background activity are almost totally neglected. The aim of the present study has been to investigate whether a special genetic type of background activity might be related to the pathogenesis of epilepsy. EEG recordings of parents of 257 epileptic children were evaluated retrospectively. Some 156 healthy adults served as controls. Special attention was paid to alpha activity extending to the frontal region, both in bipolar and in referential recordings (Alpha I). Alpha I was found significantly more often in parents of children with primary generalized epilepsy (18%) compared with parents of children with focal epilepsy (8%) or controls (9%). In a second step, parental EEGs of children with different EEG patterns associated with epilepsy were studied. Alpha I was found significantly more often in parents of children with focal sharp waves and generalized spikes and waves (26%) than in parents of probands with focal sharp waves without additional generalized spikes and waves (8%) or in controls (9%). Parents of probands with theta rhythms and spikes and waves had alpha I significantly more often (18%) than parents of probands with theta rhythms without additional spikes and waves (8%) or controls (9%). The findings reveal a clear correlation between the type of EEG background activity in parents and the EEG characteristics in their children, thus pointing to common mechanisms.     

Increasing genotype-phenotype model determinism: application to bivariate reading/language traits and epistatic interactions in language-impaired families

While advances in network and pathway analysis have flourished in the era of genome-wide association analysis, understanding the genetic mechanism of individual loci on phenotypes is still readily accomplished using genetic modeling approaches. Here, we demonstrate two novel genotype-phenotype models implemented in a flexible genetic modeling platform. The examples come from analysis of families with specific language impairment (SLI), a failure to develop normal language without explanatory factors such as low IQ or inadequate environment. In previous genome-wide studies, we observed strong evidence for linkage to 13q21 with a reading phenotype in language-impaired families. First, we elucidate the genetic architecture of reading impairment and quantitative language variation in our samples using a bivariate analysis of reading impairment in affected individuals jointly with language quantitative phenotypes in unaffected individuals. This analysis largely recapitulates the baseline analysis using the categorical trait data (posterior probability of linkage (PPL) = 80%), indicating that our reading impairment phenotype captured poor readers who also have low language ability. Second, we performed epistasis analysis using a functional coding variant in the brain-derived neurotrophic factor (BDNF) gene previously associated with reduced performance on working memory tasks. Modeling epistasis doubled the evidence on 13q21 and raised the PPL to 99.9%, indicating that BDNF and 13q21 susceptibility alleles are jointly part of the genetic architecture of SLI. These analyses provide possible mechanistic insights for further cognitive neuroscience studies based on the models developed herein.     

Evaluation of results from genome‐wide studies of language and reading in a novel independent dataset

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

Approaches to familial aggregation: hypothesis testing and estimation when families are selected through parent probands under a variant of single ascertainment

Epidemiologic approaches to testing and estimating familial aggregation of a disease consist of comparing rates of disease in relatives of individuals with the disease (known as case probands) with rates of disease in relatives of individuals without the disease (known as control probands). Gold et al. (J Am Stat Ass 1967;62: 409-420) derived an explicit mathematical model and sampling methods, under which this approach is equivalent to testing the null hypotheses that the disease risk in families is homogenous. A basic assumption of this model is that every family member has the same risk of disease and that disease status is independent among family members, although the disease risk may vary between families. When the disease is suspected of having a genetic component, rather than being purely environmental, this model has been shown to be appropriate for detecting disease aggregation in siblings, when relatives are siblings of probands. This model however is unrealistic for use in nuclear families when the affected status of offspring is not independent of the affected status of parents, and these families are selected through an affected or an unaffected parent, so that a parent is the proband and relatives are offspring of probands. We extend the Gold et al. model to allow for the disease risk in offspring to vary with the affected status of the parent. We assume that families are selected through affected and unaffected parents, under a variation of single ascertainment. Under this study design, we show that the usual test of association between affected status of probands and relatives, performed by comparing sample proportions of affected relatives of affected and unaffected probands, respectively, is no longer equivalent to a test of homogeneity of disease risk in offspring. Instead, it is equivalent to testing that the disease risk in offspring is independent of the number of affected parents. This test reduces to a test of homogeneity if and only if one assumes that the variation in disease risk in offspring, between families, is solely due to the variation in the number of affected parents. As a result, we show that under this study design, the standard chi2 test must be modified in order to obtain a valid test of familial aggregation. In addition the sample proportions of affected relatives of case and control probands, respectively, are shown to provide unbiased estimates of the expected risk of disease in an offspring given an affected/unaffected parent. We apply these results to methods of sample selection and discuss the practical implications of these findings.     

When words fail us: insights into language processing from developmental and acquired disorders

Acquired disorders of language represent loss of previously acquired skills, usually with relatively specific impairments. In children with developmental disorders of language, we may also see selective impairment in some skills; but in this case, the acquisition of language or literacy is affected from the outset. Because systems for processing spoken and written language change as they develop, we should beware of drawing too close a parallel between developmental and acquired disorders. Nevertheless, comparisons between the two may yield new insights. A key feature of connectionist models simulating acquired disorders is the interaction of components of language processing with each other and with other cognitive domains. This kind of model might help make sense of patterns of comorbidity in developmental disorders. Meanwhile, the study of developmental disorders emphasizes learning and change in underlying representations, allowing us to study how heterogeneity in cognitive profile may relate not just to neurobiology but also to experience. Children with persistent language difficulties pose challenges both to our efforts at intervention and to theories of learning of written and spoken language. Future attention to learning in individuals with developmental and acquired disorders could be of both theoretical and applied value.