Abstract:
Predicting genotype-to-phenotype correlations from genomic variants has been challenging, particularly for genes that have a complex balance of dominant and recessive inheritance for phenotypes. Variants in NMDA receptor components GRIN1, GRIN2A, and GRIN2B cause a myriad of dominant disease phenotypes, with the most common being epilepsy and autism spectrum disorder. Starting from the analysis of a variant of uncertain significance (VUS, GRIN2A G760S), we realized the need for tools to map dominant variants for the components of the NMDA receptor. Some variants within GRIN1, GRIN2A, and GRIN2B exert dominant epilepsy and developmental delay, yet other amino acid variants are conserved and predicted to alter protein function but do not have dominant phenotypes. Common variant annotation tools are not powered to determine pathogenic dominant outcomes. To address this gap, we integrated sequence and structural analyses for GRIN1, GRIN2A, and GRIN2B. Using this approach, we determined that paralog homology mapping and topology can segregate dominant variants, with an elevation of intermolecular contacts between the subunits. Furthermore, demonstrating the general utility of our methodology, we show that 25 VUS within ClinVar also reach a dominant variant annotation, including the GRIN2A G760S variant. Our work suggests paralog homology and protein topology as a powerful strategy within the receptor complex to resolve dominant genetic variants relative to variants that would fit a recessive inheritance, requiring two damaging variants. These strategies should be tested in additional dominant genetic disorders to determine the broader utility.
摘要:
从基因组变异中预测基因型与表型的相关性一直具有挑战性,特别是对于表型具有显性和隐性遗传复杂平衡的基因。NMDA受体组分GRIN1、GRIN2A、和GRIN2B引起无数的显性疾病表型,最常见的是癫痫和自闭症谱系障碍。从分析不确定意义的变体(VUS,GRIN2AG760S),我们意识到需要工具来映射NMDA受体组分的显性变异。GRIN1、GRIN2A、和GRIN2B发挥显性癫痫和发育迟缓,还有其他氨基酸变体是保守的,预计会改变蛋白质功能,但不具有显性表型。常见的变体注释工具无法确定致病性显性结果。为了解决这个差距,我们整合了GRIN1,GRIN2A,和GRIN2B。使用这种方法,我们确定旁系同源性作图和拓扑可以分离显性变异,亚单位之间的分子间接触升高。此外,证明了我们方法的普遍实用性,我们显示ClinVar中的25个VUS也达到了显性变体注释,包括GRIN2AG760S变体。我们的工作表明,同源同源物和蛋白质拓扑结构是受体复合物中解决显性遗传变异相对于适合隐性遗传的变异的强大策略。需要两个破坏性的变体。这些策略应在其他显性遗传疾病中进行测试,以确定更广泛的用途。