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

Abstract

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

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

“…An overlapping homozygous region on 14q was reported in consanguineous Pakistani families with language deficits, phenotyped with a vocabulary measure [ 19 ]. Additionally, among previously reported regions with an LOD scores greater than 1.2, 13q14 was observed in family 489 [ 17 , 20 ]. Multiple reports of overlapping loci, consistent with our findings in family 489, warranted further investigation through next generation sequencing (NGS).…”

“…Both groups replicated these findings in additional families, motivating further investigation [ 13 , 15 , 16 ]. We recently reported suggestive evidence of linkage at 4q31.23–q35.2, 14q11.2–q13.3, and 15q24.3–q25.3 to SLI in three independent families [ 17 ]. The 14q region was observed in a family with eight affected members (family 489); whole-exome sequencing (WES) in this family served as the starting point for the current study [ 17 ].…”

“…We recently reported suggestive evidence of linkage at 4q31.23–q35.2, 14q11.2–q13.3, and 15q24.3–q25.3 to SLI in three independent families [ 17 ]. The 14q region was observed in a family with eight affected members (family 489); whole-exome sequencing (WES) in this family served as the starting point for the current study [ 17 ]. Notably, the 14q region overlapped with a significant paternal parent-of-origin effect in SLIC probands and the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [ 18 ].…”

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

“…An exome sequencing analysis was conducted in six pedigrees of SLI probands with multiple affected members per family, selected from an ongoing longitudinal study in the Midwestern USA ( 95 , 96 ). The full results of this screening will be reported in a separate manuscript.…”

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

“…An exome sequencing analysis was conducted in six pedigrees of SLI probands with multiple affected members per family, selected from an ongoing longitudinal study in the Midwestern United States (53,54). The full results of this screening will be reported in a separate manuscript.…”