Neurobehavioral phenotype of Kabuki syndrome: Anxiety is a common feature.
Neurobehavioral phenotype of Kabuki syndrome: Anxiety is a common feature.
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DOI：
10.3389/fgene.2022.1007046
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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歌舞伎综合征（KS）是一种孟德尔表观遗传机制障碍（MDEM），由参与组蛋白甲基化调控的两个基因KMT 2D（34-76%）或KDM 6A（9-13%）中的任何一个基因的功能缺失变体引起。以前，KS的代表性神经行为缺陷在小鼠模型中被重现，强调KMT 2D在脑发育中的作用，特别是在齿状回颗粒细胞层中正在进行的海马神经发生中。有趣的是，焦虑，一种已知与海马神经发生减少相关的表型，在KS患者中有报道。在这项研究中，通过问卷（SCARED/GAS-ID和CBCL/ABCL）评估了60名分子证实的KS患者和25名未受影响的生物学兄弟姐妹的焦虑和行为。参与者的年龄从4岁到43岁不等，其中88.3%的参与者在KMT 2D中具有致病性变体，其余的参与者在KDM 6A中具有变体。此外，使用适当的在线调查（包括ABAS-III和PROMIS Positive Affect）收集了KS参与者的适应功能和积极情感/生活质量数据。调查分数进行了比较，在KS参与者之间的年龄组和KS参与者和他们的未受影响的兄弟姐妹。我们发现，KS患儿的焦虑评分和总行为问题评分显著高于其未受影响的兄弟姐妹（p = 0.0225，p < 0.0001）。此外，很大一部分受影响的个体（22.2%的儿童和60.0%的成人）超过了既定的焦虑阈值;考虑到许多患者已经接受了焦虑治疗，这甚至可能是低估。在这个样本中，焦虑水平与任何KS参与者的认知或适应功能水平无关，但与KS儿童的积极影响呈负相关（p = 0.0005）。这些结果表明，焦虑是一个共同的神经行为特征的KS。因此，提供者应该仔细筛查患有KS的焦虑和其他行为问题，以便及时干预。神经行为焦虑的措施也可能被证明是重要的成果措施，在KS的临床试验。
Kabuki syndrome (KS) is a Mendelian Disorder of the Epigenetic Machinery (MDEM) caused by loss of function variants in either of two genes involved in the regulation of histone methylation, KMT2D (34–76%) or KDM6A (9–13%). Previously, representative neurobehavioral deficits of KS were recapitulated in a mouse model, emphasizing the role of KMT2D in brain development, specifically in ongoing hippocampal neurogenesis in the granule cell layer of the dentate gyrus. Interestingly, anxiety, a phenotype that has a known association with decreased hippocampal neurogenesis, has been anecdotally reported in individuals with KS. In this study, anxiety and behavior were assessed in a cohort of 60 individuals with molecularly confirmed KS and 25 unaffected biological siblings, via questionnaires (SCARED/GAS-ID and CBCL/ABCL). Participant age ranged from 4 to 43 years old, with 88.3% of participants having a pathogenic variant in KMT2D, and the rest having variants in KDM6A. In addition, data was collected on adaptive function and positive affect/quality of life in participants with KS using appropriate online surveys including ABAS-III and PROMIS Positive Affect. Survey scores were compared within the KS participants across age groups and between KS participants and their unaffected siblings. We found that children with KS have significantly higher anxiety scores and total behavior problem scores than their unaffected siblings (p = 0.0225, p < 0.0001). Moreover, a large proportion of affected individuals (22.2% of children and 60.0% of adults) surpassed the established threshold for anxiety; this may even be an underestimate given many patients are already treated for anxiety. In this sample, anxiety levels did not correlate with level of cognitive or adaptive function in any KS participants, but negatively correlated with positive affect in children with KS (p = 0.0005). These findings indicate that anxiety is a common neurobehavioral feature of KS. Providers should therefore carefully screen individuals with KS for anxiety as well as other behavioral issues in order to allow for prompt intervention. Neurobehavioral anxiety measures may also prove to be important outcome measures for clinical trials in KS.
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