Judy F. Flax

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.

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.

Functional connectivity of the sensorimotor area in naturally sleeping infants

Patterns of cortical functional connectivity in normal infants were examined during natural sleep by observing the time course of very low frequency oscillations. Such oscillations represent fluctuations in blood oxygenation level and cortical blood flow thus allowing computation of neurophysiologic connectivity. Structural and resting-state information were acquired for 11 infants, with a mean age of 12.8 months, using a GE 1.5 T MR scanner. Resting-state data were processed and significant functional connectivity within the sensorimotor area was identified using independent component analysis. Unilateral functional connectivity in the developing sensory-motor cortices was observed. Power spectral analysis showed that slow frequency oscillations dominated the hemodynamic signal at this age, with, on average, a peak frequency for all subjects of 0.02 Hz. Our data suggest that there is more intrahemispheric than interhemispheric connectivity in the sensorimotor area of naturally sleeping infants. This non-invasive imaging technique, developed to allow reliable scanning of normal infants without sedation, enabled computation of neurophysiologic connectivity for the first time in naturally sleeping infants. Such techniques permit elucidation of the role of slow cortical oscillations during early brain development and may reveal critical information regarding the normative development and lateralization of brain networks across time.

Assessment of Functional Development in Normal Infant Brain using Arterial Spin Labeled Perfusion MRI

Arterial spin labeled (ASL) perfusion MRI provides a noninvasive approach for longitudinal imaging of regional brain function in infants. In the present study, continuous ASL (CASL) perfusion MRI was carried out in normally developing 7- and 13-month-old infants while asleep without sedation. The 13-month infant group showed an increase (P<0.05) of relative CBF in frontal regions as compared to the 7-month group using a region of interest based analysis. Using a machine-learning algorithm to automatically classify the relative CBF maps of the two infant groups, a significant (P<0.05, permutation testing) regional CBF increase was found in the hippocampi, anterior cingulate, amygdalae, occipital lobes, and auditory cortex in the 13-month-old infants. These results are consistent with current understanding of infant brain development and demonstrate the feasibility of using perfusion MRI to noninvasively monitor developing brain function.

Relations between prosodic variables and communicative functions.

Three children were observed interacting with their mothers at three different times: before the onset of single words, when vocabulary consisted of 10 words, and when vocabulary consisted of 50 words. Relations between communicative functions and acoustic analyses of prosodic variables (i.e. rise vs. nonrise of terminal contours) were studied. Considerable variability was found among the children in the number of rises produced overall and those produced for any function. Each childs use of rise was fairly constant over time and rises were produced relatively more frequently than nonrises with functions requiring a response from the listener. Factors affecting similarities and differences are discussed.

Associations between the size of the amygdala in infancy and language abilities during the preschool years in normally developing children

Recently, structural MRI studies in children have been used to examine relations between brain volume and behavioral measures. However, most of these studies have been done in children older than 2 years of age. Obtaining volumetric measures in infants is considerably more difficult, as structures are less well defined and largely unmyelinated, making segmentation challenging. Moreover, it is still unclear whether individual anatomic variation across development, in healthy, normally developing infants, is reflected in the configuration and function of the mature brain and, as importantly, whether variation in infant brain structure might be related to later cognitive and linguistic abilities. In this longitudinal study, using T1 structural MRI, we identified links between amygdala volume in normally developing, naturally sleeping, 6-month infants and their subsequent language abilities at 2, 3 and 4 years. The images were processed and manually segmented using Cardviews to extract volumetric measures. Intra-rater reliability for repeated segmentation was 87.73% of common voxel agreement. Standardized language assessments were administered at 6 and 12 months and at 2, 3 and 4 years. Significant and consistent correlations were found between amygdala size and language abilities. Children with larger right amygdalae at 6 months had lower scores on expressive and receptive language measures at 2, 3, and 4 years. Associations between amygdala size and language outcomes have been reported in children with autism. The findings presented here extend this association to normally developing children, supporting the idea that the amygdalae might play an important but as yet unspecified role in mediating language acquisition.

Using Early Standardized Language Measures to Predict Later Language and Early Reading Outcomes in Children at High Risk for Language-Learning Impairments

The aim of the study was to examine the profiles of children with a family history (FH+) of language-learning impairments (LLI) and a control group of children with no reported family history of LLI (FH—) and identify which language constructs (receptive or expressive) and which ages (2 or 3 years) are related to expressive and receptive language abilities, phonological awareness, and reading abilities at ages 5 and 7 years. Participants included 99 children (40 FH+ and 59 FH—) who received a standardized neuropsychological battery at 2, 3, 5, and 7 years of age. As a group, the FH+ children had significantly lower scores on all language measures at 2 and 3 years, on selected language and phonological awareness measures at 5 years, and on phonological awareness and nonword reading at 7 years. Language comprehension at 3 years was the best predictor of later language and early reading for both groups. These results support past work suggesting that children with a positive family history of LLI are at greater risk for future language and reading problems through their preschool and early school-age years. Furthermore, language comprehension in the early years is a strong predictor of future language-learning status.

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.

Genetic Covariation Underlying Reading, Language and Related Measures in a Sample Selected for Specific Language Impairment

Specific language impairment is a developmental language disorder characterized by failure to develop language normally in the absence of a specific cause. Previous twin studies have documented the heritability of reading and language measures as well as the genetic correlation between those measures. This paper presents results from an alternative to the classical twin designs by estimating heritability from extended pedigrees. These pedigrees were previously studied as part of series of molecular genetic studies of specific language impairment where the strongest genetic findings were with reading phenotypes rather than language despite selecting pedigrees based on language impairments. To explore the relationship between reading and language in these pedigrees, variance components estimates of heritability of reading and language measures were conducted showing general agreement with the twin literature, as were genetics correlations between reading and language. Phonological short-term memory, phonological awareness and auditory processing were evaluated as candidate mediators of the reading-language genetic correlations. Only phonological awareness showed significant genetic correlations with all reading measures and several language measures while phonological short-term memory and auditory processing did not.

Gene Gene Interaction in Shared Etiology of Autism and Specific Language Impairment

BACKGROUND To examine the relationship between autism spectrum disorders (ASD) and specific language impairment (SLI), family studies typically take a comparative approach where families with one disease are examined for traits of the other disease. In contrast, the present report is the first study with both disorders required to be present in each family to provide a more direct test of the hypothesis of shared genetic etiology. METHODS We behaviorally assessed 51 families including at least one person with ASD and at least one person with SLI (without ASD). Pedigree members were tested with 22 standardized measures of language and intelligence. Because these extended families include a nonshared environmental contrast, we calculated heritability, not just familiality, for each measure twice: 1) baseline heritability analysis, compared with; 2) heritability estimates after statistically removing ASD subjects from pedigrees. RESULTS Significant increases in heritability on four supra-linguistic measures (including Pragmatic Judgment) and a composite language score but not on any other measures were observed when removing ASD subjects from the analysis, indicating differential genetic effects that are unique to ASD. Nongenetic explanations such as effects of ASD severity or measurement error or low score variability in ASD subjects were systematically ruled out, leaving the hypothesis of nonadditive genetics effects as the potential source of the heritability change caused by ASD. CONCLUSIONS Although the data suggest genetic risk factors common to both SLI and ASD, there are effects that seem unique to ASD, possibly caused by nonadditive gene-gene interactions of shared risk loci.