EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction
EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction
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DOI：
10.1186/s13229-018-0193-9
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发表时间：
2018-01-25
期刊：
影响因子：
6.2
通讯作者：
Kleefstra, Tjitske
中科院分区：
文献类型：
--
作者：
de Boer, Anneke;Vermeulen, Karlijn;Kleefstra, Tjitske
背景：只有在没有明显的健康或发育问题的情况下，才能偶尔发现遗传嵌合体。大多数病例涉及健康的父母，他们通过对最初在孩子身上发现的基因缺陷进行有针对性的测试，发现他们患有马赛克。影响常染色素组蛋白甲基转移酶1(EHMT1)基因的种系遗传缺陷导致Kleefstra综合征，该综合征与典型的三联症有关，包括明显的面部外观、(童年)低眼压和智力残疾。高度的精神病理与这种综合征有关。在一名儿童被诊断出患有生殖系EHMT1缺陷后，一些父母在检测中发现了嵌合体EHMT1突变。乍一看，嵌合型EHMT1突变的携带者似乎功能正常。然而，最近的研究表明，重要发育基因的从头开始、合子后突变显著地导致自闭症谱系障碍(ASD)。因此，我们假设EHMT1嵌合体可能导致神经精神缺陷。为了研究这一点，我们对确诊为EHMT1嵌合症的父母进行了详细的神经精神参数调查。方法：对3名经基因诊断为EHMT1嵌合症的成年人(2名男性，1名女性)进行了一系列测试和观察仪器的检查，包括神经认知和精神特征。该组合包括以下工具：自闭症诊断观察表(ADOS)、成人发育障碍迷你精神病学评估表(mini PAS-ADD)、Vineland适应行为量表(VABs)和剑桥神经心理测试自动化成套量表(CANAB)。这些措施与我们之前报道的Kleefstra综合征患者的数据进行了比较。结果：所有三名受试者的VAB总分都达到了最高分，表明功能正常(适应性)。总体而言，ASD的ADOS和严重抑郁障碍(LIFE)的迷你PAS-ADD得分均高于临界值。最后，CANAB上的结果显示所有受试者的认知灵活性都受到了损害。结论：患有EHMT1马赛克的人似乎更容易患上严重的精神病理，特别是自闭症和情绪障碍。尽管乍一看，他们在日常生活中似乎适应得很好，但与普通人群相比，他们可能会出现明显的精神症状，并表现出认知灵活性降低。
Background: Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism.Methods: Three adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects.Results: All three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects.Conclusion: Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population.