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

2021 ◽  
Vol 12 (1) ◽  
pp. 47
Author(s):  
Erin M. Andres ◽  
Kathleen Kelsey Earnest ◽  
Cuncong Zhong ◽  
Mabel L. Rice ◽  
Muhammad Hashim Raza
Keyword(s):  
Language Impairment ◽  
Specific Language Impairment ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
P Value ◽  
Single Family ◽  
Neural Basis ◽  
Specific Language ◽  
New Genes ◽  
Whole Exome

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.

scholarly journals Next-generation sequencing identifies novel gene variants and pathways involved in specific language impairment

2016 ◽  
Author(s):  
Xiaowei Sylvia Chen ◽  
Rose H. Reader ◽  
Alexander Hoischen ◽  
Joris A. Veltman ◽  
Nuala H. Simpson ◽  
...  
Keyword(s):  
Language Impairment ◽  
Specific Language Impairment ◽  
Significant Proportion ◽  
Substantial Impact ◽  
Specific Language ◽  
Pathogenic Variants ◽  
Cytoskeletal Regulation ◽  
Whole Exome ◽  
Multiple Hit ◽  
Candidate Loci

ABSTRACTA significant proportion of children suffer from unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. These developmental speech and language disorders are highly heritable and have a substantial impact on society. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. Here, we performed whole exome sequencing of 43 unrelated probands affected by severe forms of specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to try to shed new light on the aetiology of the disorder. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidate genes carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. When we broadened our scope to all rare and novel variants throughout the exomes, we identified several biological themes that were enriched for such variants, most notably microtubule transport and cytoskeletal regulation.

scholarly journals Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

2016 ◽  
Author(s):  
Andrea Ganna ◽  
Giulio Genovese ◽  
Daniel P. Howrigan ◽  
Andrea Byrnes ◽  
Mitja Kurki ◽  
...  
Keyword(s):  
General Population ◽  
Neurodevelopmental Disorders ◽  
Cognitive Abilities ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
P Value ◽  
Sequencing Data ◽  
Whole Exome ◽  
Number Variation

Ultra-rare inherited and de novo disruptive variants in highly constrained (HC) genes are enriched in neurodevelopmental disorders 1–5. However, their impact on cognition in the general population has not been explored. We hypothesize that disruptive and damaging ultra-rare variants (URVs) in HC genes not only confer risk to neurodevelopmental disorders, but also influence general cognitive abilities measured indirectly by years of education (YOE). We tested this hypothesis in 14,133 individuals with whole exome or genome sequencing data. The presence of one or more URVs was associated with a decrease in YOE (3.1 months less for each additional mutation; P-value=3.3×10−8) and the effect was stronger in HC genes enriched for brain expression (6.5 months less, P-value=3.4×10−5). The effect of these variants was more pronounced than the estimated effects of runs of homozygosity and pathogenic copy number variation 6–9. Our findings suggest that effects of URVs in HC genes are not confined to severe neurodevelopmental disorder, but influence the cognitive spectrum in the general population

The Role of Early Auditory Discrimination Deficits in Language Disorders

2007 ◽  
Vol 21 (3-4) ◽  
pp. 239-250 ◽  
Author(s):  
Teija Kujala
Keyword(s):  
Language Impairment ◽  
Specific Language Impairment ◽  
Language Disorders ◽  
Autism Spectrum ◽  
Auditory Discrimination ◽  
Language Impairments ◽  
Neural Basis ◽  
Specific Language ◽  
Early Stages ◽  
Language Problems

Language impairments can have a devastating effect on the individual’s life. Brain damage such as stroke may cause varying degrees of impaired language. Even milder language problems, such as developmental dyslexia or specific language impairment, can have long-lasting detrimental effects on the individual’s life, affecting both success at school as well as motivation and even self-esteem. In recent years, the mismatch negativity (MMN) has been intensively applied to study the neural basis of language impairments. These studies have shown that the MMN, which reflects the early stages of cortical sound discrimination, is abnormal in a large variety of language impairments. Furthermore, a close relationship between the MMN and some language disorders is suggested by significant correlations between the MMN and language test results. Further support is provided by follow-up studies suggesting that the MMN parameters may predict future language problems in children and by investigations indicating that intervention programs with an ameliorating effect also concurrently change the MMN. However, when interpreting the implications of MMN results it is important to acknowledge that this response specifically reflects early stages of auditory discrimination and should, therefore, be combined with measures probing the further steps of auditory processing for a more complete picture of the underlying deficits of language. The current review addresses how the MMN can be used in determining auditory impairments in language disorders such as aphasia, dyslexia, autism spectrum, and specific language impairment.

Eliciting Verbs From Children With Specific Language Impairment

1996 ◽  
Vol 5 (4) ◽  
pp. 17-30 ◽  
Author(s):  
Diane Frome Loeb ◽  
Clifton Pye ◽  
Sean Redmond ◽  
Lori Zobel Richardson
Keyword(s):  
Young Children ◽  
Language Impairment ◽  
Specific Language Impairment ◽  
Syntactic Complexity ◽  
Specific Language ◽  
Lexical Skills

The focus of assessment and intervention is often aimed at increasing the lexical skills of young children with language impairment. Frequently, the use of nouns is the center of the lexical assessment. As a result, the production of verbs is not fully evaluated or integrated into treatment in a way that accounts for their semantic and syntactic complexity. This paper presents a probe for eliciting verbs from children, describes its effectiveness, and discusses the utility of and problems associated with developing such a probe.

Deficits in Explicit Language Problem Solving Rather Than in Implicit Learning in Specific Language Impairment: Evidence From Learning an Artificial Morphological Rule

2019 ◽  
Vol 62 (10) ◽  
pp. 3790-3807 ◽  
Author(s):  
Sara Ferman ◽  
Liat Kishon-Rabin ◽  
Hila Ganot-Budaga ◽  
Avi Karni
Keyword(s):  
Language Learning ◽  
Language Impairment ◽  
Specific Language Impairment ◽  
Explicit Knowledge ◽  
Procedural Memory ◽  
Procedural Learning ◽  
Specific Language ◽  
Language Problems ◽  
Morphological Rule ◽  
Semantic Distinction

Purpose The purpose of this study was to delineate differences between children with specific language impairment (SLI), typical age–matched (TAM) children, and typical younger (TY) children in learning and mastering an undisclosed artificial morphological rule (AMR) through exposure and usage. Method Twenty-six participants (eight 10-year-old children with SLI, 8 TAM children, and ten 8-year-old TY children) were trained to master an AMR across multiple training sessions. The AMR required a phonological transformation of verbs depending on a semantic distinction: whether the preceding noun was animate or inanimate. All participants practiced the application of the AMR to repeated and new (generalization) items, via judgment and production tasks. Results The children with SLI derived significantly less benefit from practice than their peers in learning most aspects of the AMR, even exhibiting smaller gains compared to the TY group in some aspects. Children with SLI benefited less than TAM and even TY children from training to judge and produce repeated items of the AMR. Nevertheless, despite a significant disadvantage in baseline performance, the rate at which they mastered the task-specific phonological regularities was as robust as that of their peers. On the other hand, like 8-year-olds, only half of the SLI group succeeded in uncovering the nature of the AMR and, consequently, in generalizing it to new items. Conclusions Children with SLI were able to learn language aspects that rely on implicit, procedural learning, but experienced difficulties in learning aspects that relied on the explicit uncovering of the semantic principle of the AMR. The results suggest that some of the difficulties experienced by children with SLI when learning a complex language regularity cannot be accounted for by a broad, language-related, procedural memory disability. Rather, a deficit—perhaps a developmental delay in the ability to recruit and solve language problems and establish explicit knowledge regarding a language task—can better explain their difficulties in language learning.

A View of the Lexical–Grammatical Link in Young Latinos With Specific Language Impairment Using Language-Specific and Conceptual Measures

2019 ◽  
Vol 62 (6) ◽  
pp. 1775-1786 ◽  
Author(s):  
Lucía I. Méndez ◽  
Gabriela Simon-Cereijido
Keyword(s):  
Low Income ◽  
Language Impairment ◽  
Specific Language Impairment ◽  
L2 Acquisition ◽  
Cross Sectional ◽  
Specific Language ◽  
Vocabulary Skills ◽  
In The Beginning ◽  
Study Participants ◽  
L1 And L2

Purpose This study investigated the nature of the association of lexical–grammatical abilities within and across languages in Latino dual language learners (DLLs) with specific language impairment (SLI) using language-specific and bilingual measures. Method Seventy-four Spanish/English–speaking preschoolers with SLI from preschools serving low-income households participated in the study. Participants had stronger skills in Spanish (first language [L1]) and were in the initial stages of learning English (second language [L2]). The children's lexical, semantic, and grammar abilities were assessed using normative and researcher-developed tools in English and Spanish. Hierarchical linear regressions of cross-sectional data were conducted using measures of sentence repetition tasks, language-specific vocabulary, and conceptual bilingual lexical and semantic abilities in Spanish and English. Results Results indicate that language-specific vocabulary abilities support the development of grammar in L1 and L2 in this population. L1 vocabulary also contributes to L2 grammar above and beyond the contribution of L2 vocabulary skills. However, the cross-linguistic association between vocabulary in L2 and grammar skills in the stronger or more proficient language (L1) is not observed. In addition, conceptual vocabulary significantly supported grammar in L2, whereas bilingual semantic skills supported L1 grammar. Conclusions Our findings reveal that the same language-specific vocabulary abilities drive grammar development in L1 and L2 in DLLs with SLI. In the early stages of L2 acquisition, vocabulary skills in L1 also seem to contribute to grammar skills in L2 in this population. Thus, it is critical to support vocabulary development in both L1 and L2 in DLLs with SLI, particularly in the beginning stages of L2 acquisition. Clinical and educational implications are discussed.

Sign in / Sign up

Export Citation Format

Share Document