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Family-based genetic investigation of SLI (Andres et al., 2020)

journal contribution
posted on 2020-11-13, 23:01 authored by Erin M. Andres, Kathleen Kelsey Earnest, Shelley D. Smith, Mabel L. Rice, Muhammad Hashim Raza
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 Figure S1. Genome-wide linkage results for all six families.

Supplemental Figure S2. Linkage analysis separately in Branch 1, Branch 2, and Branch 3 and all possible combinations of these branches.

Supplemental Table S1. Previously reported chromosomal loci linked to related phenotypes showing single point logarithm of odds (LOD) scores > 1.2.

Supplemental Table S2. Genes in the suggestive linkage region chr4:154,887,604-179,989,221 (chr4q31.3-q34.3).

Supplemental Table S3. Genes in the suggestive linkage region chr15:68,679,181-83,215,251 (chr15q23-q25.2).

Supplemental Table S4. Genes in the linkage region chr14:20,825,965-37,059,525 (chr14q11.2-q13.3).

Supplemental Table S5. Additional single nucleotide polymorphisms (SNPs) with single-point logarithm of odds (LOD) scores > 2.0 in family 315 genome-wide.

Andres, E. M., Earnest, K. K., Smith, S. D., Rice, M. L., & Raza, M. H. (2020). Pedigree-based gene mapping supports previous loci and reveals novel suggestive loci in specific language impairment. Journal of Speech, Language, and Hearing Research. Advance online publication.


This work was supported by the National Institute on Deafness and Other Communication Disorders awarded to M. L. R. (T32DC000052, R01DC001803) and M. H. R. (R21 DC017830). This work was also supported in part by the start-up research funds and Research Excellence Initiative-Child Language Doctoral Program funds provided to M. H. R. by the KU, Lawrence.