Whole exome sequencing in a large Swedish cohort with severe developmental language disorders

Abstract

BackgroundDevelopmental language disorder (DLD) constitutes a relatively common form of neurodevelopmental disorder (NDD) that receives little research attention. Recent evidence indicated that genetic factors, especially rare variants, are significant in the pathogenesis of DLD. DLD overlaps clinically, genetically, and pathologically with other NDD, corroborating the concept of NDD continuum.MethodsPreviously we examined 58 probands with severe DLD and their families using microarray genotyping and identified clinically significant copy number variants in four probands resulting in 6.9% molecular diagnostic yield. In the current study, we investigated 53 of those probands using whole exome sequencing followed by downstream bioinformatic analysis, confirmatory Sanger sequencing, and segregation analysis when possible.ResultsWe identified clinically significant variants in five probands, resulting in 9.4% (5/53) molecular diagnostic yield. Those clinically significant variants were in CHD3, PAK2, MED13, PLCB4, and TNRC6B. We also identified high-impact variants in PARD3 and DIP2C genes that have less established associations with DLD/NDD, and in five more genes (TXLNA, APBA1, AQR, ZBTB38, and one gene in-process of functional validation) not previously known as risk/causative DLD/NDD genes.ConclusionOur study adds to the limited landscape of genetic studies in DLD and provides evidence that next-generation sequencing with or without array genotyping should be offered to children with DLD, particularly severe DLD. We also further highlighted the potential of whole exome sequencing for identifying novel DLD genes.