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. 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. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in 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. We did not detect significant associations between the language-related tests and language-related PRS. 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 condition.

发育性语言障碍 (DLD) 在临床、遗传和病理学上与其他神经发育障碍 (NDD) 重叠，证实了 NDD 连续体的概念。目前缺乏了解 DLD 患者整个基因谱的研究。此前，我们从 59 个家庭招募了 61 名患有严重 DLD 的先证者，并使用微阵列基因分型对其中 59 名及其家人进行了检查，诊断率为 6.8%。在此，我们使用全外显子组测序 (WES) 对其中 53 名先证者进行了研究。此外，我们使用多基因风险评分（PRS）来了解神经发育困难的家族内丰富性，并检查先证者语言相关测试结果与语言相关 PRS 之间的关联。我们在 4 名先证者中发现了具有临床意义的变异，从而获得了 7.5% (4/53) 的分子诊断率。这些变体存在于PAK2、MED13、PLCB4和TNRC6B中。我们还优先考虑了未来研究中其他变体在 DLD 中的作用，包括PARD3和DIP2C中的高影响力变体。PRS 并没有解释这些家庭中神经发育困难的聚集。我们没有发现语言相关测试和语言相关 PRS 之间存在显着关联。我们的结果支持使用 WES 作为 DLD 的一级基因测试，因为它可以识别单基因 DLD 形式。需要对 DLD 进行大规模测序研究来识别新基因并研究多基因对该疾病的影响。