Abstract：
OBJECTIVE: Rare genetic variants in the PURA gene cause the PURA-related neurodevelopmental disorder (PURA-NDD), characterized by neonatal abnormalities and developmental delay. Using genome-wide DNA methylation analysis on patients with PURA variants, we aim to establish a PURA-NDD-specific methylation profile and provide further insights on the molecular basis of the PURA-NDD.
METHODS: Twenty three individuals (including 12 unpublished) carrying PURA variants were enrolled. We conducted the Illumina Infinium EPIC microarray analysis in 17 PURA-NDD individuals. In vitro experiments were performed to examine how PURA variants affect Pur-a expression.
RESULTS: Additional phenotypes in 12 newly identified patients were described in this study. Genome-wide DNA methylation analysis unveiled distinctive methylation profiles to PURA-NDD, and the established classifier can reclassify PURA variants of uncertain significance. Patients bearing PURA hapoloinsufficient and missense variants have comparable DNA methylation profiles, and cells expressing these PURA variants showed consistent Pur-a downregulation, suggesting a haploinsufficiency mechanism.
CONCLUSIONS: Patients with PURA-NDD exhibit a specific episignature, which has potential to aid identification and diagnosis of PURA-NDD patients and offer implications for further functional investigations.
METHODS: Twenty three individuals (including 12 unpublished) carrying PURA variants were enrolled. We conducted the Illumina Infinium EPIC microarray analysis in 17 PURA-NDD individuals. In vitro experiments were performed to examine how PURA variants affect Pur-a expression.
RESULTS: Additional phenotypes in 12 newly identified patients were described in this study. Genome-wide DNA methylation analysis unveiled distinctive methylation profiles to PURA-NDD, and the established classifier can reclassify PURA variants of uncertain significance. Patients bearing PURA hapoloinsufficient and missense variants have comparable DNA methylation profiles, and cells expressing these PURA variants showed consistent Pur-a downregulation, suggesting a haploinsufficiency mechanism.
CONCLUSIONS: Patients with PURA-NDD exhibit a specific episignature, which has potential to aid identification and diagnosis of PURA-NDD patients and offer implications for further functional investigations.
摘要：
目的：PURA基因中的罕见遗传变异导致PURA相关神经发育障碍（PURA-NDD），以新生儿异常和发育迟缓为特征。使用全基因组DNA甲基化分析对患有PURA变异的患者，我们的目标是建立PURA-NDD特异性甲基化谱，并提供对PURA-NDD分子基础的进一步见解。
方法：纳入了23名携带PURA变异体的个体（包括12名未发表的个体）。我们对17名PURA-NDD个体进行了IlluminaInfiniumEPIC微阵列分析。进行体外实验以检查PURA变体如何影响Pur-α表达。
结果：本研究描述了12名新发现的患者的其他表型。全基因组DNA甲基化分析揭示了PURA-NDD独特的甲基化谱，建立的分类器可以对不确定意义的PURA变体进行重新分类。带有PURAhapolocomfortness和错义变异的患者具有可比的DNA甲基化倾向，表达这些PURA变体的细胞显示出一致的Pur-α下调，表明单倍体不足机制。
结论：PURA-NDD患者表现出特定的epi特征，这有可能帮助鉴定和诊断PURA-NDD患者，并为进一步的功能调查提供启示。
方法：纳入了23名携带PURA变异体的个体（包括12名未发表的个体）。我们对17名PURA-NDD个体进行了IlluminaInfiniumEPIC微阵列分析。进行体外实验以检查PURA变体如何影响Pur-α表达。
结果：本研究描述了12名新发现的患者的其他表型。全基因组DNA甲基化分析揭示了PURA-NDD独特的甲基化谱，建立的分类器可以对不确定意义的PURA变体进行重新分类。带有PURAhapolocomfortness和错义变异的患者具有可比的DNA甲基化倾向，表达这些PURA变体的细胞显示出一致的Pur-α下调，表明单倍体不足机制。
结论：PURA-NDD患者表现出特定的epi特征，这有可能帮助鉴定和诊断PURA-NDD患者，并为进一步的功能调查提供启示。
