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

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. https://doi.org/10.1044/2020_JSLHR-20-00102