Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.

Helsmoortel-Van der Aa 综合征 (HVDAS) 是一种与智力障碍/发育迟缓、自闭症谱系障碍和多种医学合并症相关的神经发育疾病。HVDAS 是由活性依赖性神经保护蛋白 ( ADNP ) 突变引起的）。最近的一项研究确定了 22 名 HVDAS 患者的全基因组 DNA 甲基化变化，增加了具有表观遗传特征的神经发育障碍组。这种甲基化特征根据突变的位置将具有 HVDAS 的人分为两组。在这里，我们对 24 名 HVDAS 患者进行了独立研究，并复制了两种突变依赖性表观特征的存在。为了探究这两种不同的表观特征是否与临床结果相关，我们使用了来自两个具有 HVDAS 基因诊断的前瞻性人群的深层行为和神经生物学数据。我们发现两个受 HVDAS 影响的组之间的表型差异有限，并且没有证据表明具有更广泛甲基化变化的个体受到更严重的影响。而且，尽管甲基化发生了变化，但我们观察到HVDAS个体的血液转录组没有显着变化。我们的数据值得谨慎使用HVDAS中的甲基化特征作为临床分层的工具，至少在行为表型方面是这样。