Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Abstract

Abstract Background Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Methods Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. Results We identified clinically significant variants in five probands, resulting in a 9.4% (5/53) molecular diagnostic yield. Those variants were in CHD3, PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. However, we detected positive associations between neurodevelopmental difficulties and PRS for educational attainment and cognitive performance within the families (p = 0.006 and 0.02, respectively). We did not detect significant associations between PRS for language quantitative measures and their corresponding PRS. Conclusion Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the conditions.