Longitudinal Grammaticality Judgments of Tense Marking in Complex Questions in Children With and Without Specific Language Impairment, Ages 5-18 Years.

PURPOSE: Identification of children with specific language impairment (SLI) can be difficult even though their language can lag that of age peers throughout childhood. A clinical grammar marker featuring tense marking in simple clauses is valid and reliable for young children but is limited by ceiling effects around the age of 8 years. This study evaluated a new, more grammatically challenging complex sentence task in children affected or unaffected with SLI in longitudinal data, ages 5-18 years. METHOD: Four hundred eighty-three children (213 unaffected, 270 affected) between 5 and 18 years of age participated, following a rolling recruitment longitudinal design encompassing a total of 4,148 observations. The new experimental grammaticality judgment task followed linguistic concepts of syntactic sites for finiteness and movement within complex clauses. Growth modeling methods evaluated group differences over time for four different outcomes; three were hypothesized to evaluate optional omissions of overt finiteness forms in authorized sentence sites, and one evaluated an overt error of tense marking. RESULTS: As in earlier studies of younger children, growth models for the SLI group were consistently lower than the unaffected group, although the growth trajectories across groups did not differ. The results replicated across four item types defined by omissions with minor differences for an item with an overt error of tense marking. Covariates of child nonverbal IQ, mother's education, and child sex did not significantly moderate these effects. CONCLUSION: The outcomes support the task as having potential screening value for identification of children with SLI and are consistent with linguistic interpretations of task demands.

Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment.

Individuals with specific language impairment (SLI) struggle with language acquisition despite average non-verbal intelligence and otherwise typical development. One SLI account focuses on grammar acquisition delay. The current study aimed to detect novel rare genetic variants associated with performance on a grammar assessment, the Test of Early Grammatical Impairment (TEGI), in English-speaking children. The TEGI was selected due to its sensitivity and specificity, consistently high heritability estimates, and its absence from all but one molecular genetic study. We performed whole exome sequencing (WES) in eight families with SLI (n = 74 total) and follow-up Sanger sequencing in additional unrelated probands (n = 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (n = 34) from at least two families under two filtering workflows: (1) novel and (2) previously reported candidate genes. Candidate variants were observed on six new genes (PDHA2, PCDHB3, FURIN, NOL6, IQGAP3, and BAHCC1), and two genes previously reported for overall language ability (GLI3 and FLNB). We specifically suggest PCDHB3, a protocadherin gene, and NOL6 are critical for ribosome synthesis, as they are important targets of SLI investigation. The proposed SLI candidate genes associated with TEGI performance emphasize the utility of precise phenotyping and family-based genetic study.

Family-Based Whole-Exome Analysis of Specific Language Impairment (SLI) Identifies Rare Variants in BUD13, a Component of the Retention and Splicing (RES) Complex.

Specific language impairment (SLI) is a common neurodevelopmental disorder (NDD) that displays high heritability estimates. Genetic studies have identified several loci, but the molecular basis of SLI remains unclear. With the aim to better understand the genetic architecture of SLI, we performed whole-exome sequencing (WES) in a single family (ID: 489; n = 11). We identified co-segregating rare variants in three new genes: BUD13, APLP2, and NDRG2. To determine the significance of these genes in SLI, we Sanger sequenced all coding regions of each gene in unrelated individuals with SLI (n = 175). We observed 13 additional rare variants in 18 unrelated individuals. Variants in BUD13 reached genome-wide significance (p-value < 0.01) upon comparison with similar variants in the 1000 Genomes Project, providing gene level evidence that BUD13 is involved in SLI. Additionally, five BUD13 variants showed cohesive variant level evidence of likely pathogenicity. Bud13 is a component of the retention and splicing (RES) complex. Additional supportive evidence from studies of an animal model (loss-of-function mutations in BUD13 caused a profound neural phenotype) and individuals with an NDD phenotype (carrying a CNV spanning BUD13), indicates BUD13 could be a target for investigation of the neural basis of language.

Pedigree-Based Gene Mapping Supports Previous Loci and Reveals Novel Suggestive Loci in Specific Language Impairment.

Purpose Specific language impairment (SLI) is characterized by a delay in language acquisition despite a lack of other developmental delays or hearing loss. Genetics of SLI is poorly understood. The purpose of this study is to identify SLI genetic loci through family-based linkage mapping. Method We performed genome-wide parametric linkage analysis in six families segregating with SLI. An age-appropriate standardized omnibus language measure was used to categorically define the SLI phenotype. Results A suggestive linkage region replicated a previous region of interest with the highest logarithm of odds (LOD) score of 2.40 at 14q11.2-q13.3 in Family 489. A paternal parent-of-origin effect associated with SLI and language phenotypes on a nonsynonymous single nucleotide polymorphism (SNP) in NOP9 (14q12) was reported previously. Linkage analysis identified a new SLI locus at 15q24.3-25.3 with the highest parametric LOD score of 3.06 in Family 315 under a recessive mode of inheritance. Suggestive evidence of linkage was also revealed at 4q31.23-q35.2 in Family 300, with the highest LOD score of 2.41. Genetic linkage was not identified in the other three families included in parametric linkage analysis. Conclusions These results are the first to report genome-wide suggestive linkage with a total language standard score on an age-appropriate omnibus language measure across a wide age range. Our findings confirm previous reports of a language-associated locus on chromosome 14q, report new SLI loci, and validate the pedigree-based parametric linkage analysis approach to mapping genes for SLI. Supplemental Material https://doi.org/10.23641/asha.13203218.