A Major Susceptibility Locus for Specific Language Impairment Is Located on 13q21

Abstract

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.

Strategies for Conducting Research on Language in Autism

“…In one study, the subgroup of probands with autism who had no language or clearly impaired language whose parents also had a history of language difficulties were separated from the full sample that included children without language impairment (CLSA, 2001). The linkage signals on two chromosomes, 7q and 13q, both of which have been implicated as loci for SLI (Bartlett, Flax, Logue, Vieland, Bassett, Tallal, & Brzustowicz, 2002;O'Brien, Zhang, Nishimura, Tomblin, & Murray, 2003), were significantly increased, suggesting that these signals were mainly attributable to the language-impaired subtype within autism. Similar findings were obtained in the second study by the Autism Genetic Resource Exchange Consortium (AGRE) using different definitions of language-impaired in an independent sample of autism families (Alarcon et al, 2002).…”

Family-based association study of DYX1C1 variants in autism

“…14 -16 Noteworthy, also most samples with specific language impairment (SLI) have failed to show any linkage or association signals at the FOXP2 locus, indicating that it is unlikely to play a significant role in cases of typical SLI. 14,17,18 However, one recent study showed putative evidence for association of FOXP2 locus with SLI. 19 In a Finnish dyslexia sample, linkage for 7q31 overlapping SPCH1 and AUTS1 loci was observed, but sequencing of FOXP2 in dyslexic individuals revealed no coding sequence mutations.…”

Specific language impairment in the long-term perspective – the importance of assessment procedures, reading skills, and communicative competence

“…) indicates that the conclusions from clinical and psychometric assessment criteria of SLI differ vastly. Clinical approaches may be misleading, particularly in environments with a higher risk of language impairment, for example in families where some degree of speech or language impairment is already present (Bartlett et al, 2002;Bishop, 2006;Gopnik & Crago, 1991).…”