A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electro-clinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with generalized epilepsy, behavioral issues, and various degrees of intellectual disability. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioral issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electro-clinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor over-activity is observed in a broader range of patients with neurodevelopmental disorders, since SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, since a substantial portion of available anti-seizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

中文翻译：

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GABRD 中的功能获得变异揭示了神经发育障碍和癫痫的新途径

由于早期研究得出的相互矛盾的结论，在很大程度上忽视了编码突触外 GABAA 受体的 δ 亚基的 GABRD 与神经发育障碍之间的潜在联系。然而，我们在 10 名患有神经发育障碍和全身性癫痫的患者中发现了 7 个杂合错义 GABRD 变异。一种变异发生在健康父母的两个兄弟姐妹中，推测为体细胞嵌合，另一种与疾病隔离在三个受影响的家庭成员中，其余五个发生在零星患者中。电生理测量用于确定α1β3δ和α4β2δGABAA受体的受体组合中七种错义δ亚基变体的功能结果。这伴随着对受影响个体的电临床表型的分析。我们确定七种变体中的五种导致产生的α1β3δ和α4β2δGABAA受体功能改变。令人惊讶的是，五种变体中的四种导致功能获得效应，而一种导致功能丧失效应。临床表型反映了功能获得和功能丧失效应之间的明显差异。六名具有功能获得性变异的患者具有共同的表型：神经发育障碍伴全身性癫痫、行为问题和不同程度的智力障碍。六名具有功能获得性变异的患者具有共同的表型：伴有行为问题的神经发育障碍、不同程度的智力障碍、伴有非典型缺席的全身性癫痫和全身性肌阵挛和/或双侧强直-阵挛性癫痫发作。脑电图显示不同功能增益变异携带者之间的定性相似性，包括枕区的局灶性减慢，通常在不规则的全身性癫痫样放电之前，以额叶为主。相比之下，一名携带功能丧失变异体的患者智力正常，没有癫痫病史，但被诊断为自闭症谱系障碍，并患有内化精神症状升高。我们假设由含 δ 的突触外 GABAA 受体介导的强直性 GABA 诱发电流水平的增加导致异常的神经传递，这代表了严重神经发育障碍的新机制。为了支持这一点，功能获得性 GABRD 变体的电临床发现类似于错义 SLC6A1（GABA 摄取转运蛋白）变体患者报告的表型谱。这也表明在更广泛的神经发育障碍患者中观察到突触外受体过度活跃的现象，因为 SLC6A1 功能丧失变异体也导致过度活跃的含突触外 δ GABAA 受体。这些发现在选择潜在治疗方案时具有重要意义，因为大部分可用的抗癫痫药物通过直接或间接增强 GABA 能功能发挥作用，这可能会加剧功能获得性 GABRD 变异患者的症状。这也表明在更广泛的神经发育障碍患者中观察到突触外受体过度活跃的现象，因为 SLC6A1 功能丧失变异体也导致过度活跃的含突触外 δ GABAA 受体。这些发现在选择潜在治疗方案时具有重要意义，因为大部分可用的抗癫痫药物通过直接或间接增强 GABA 能功能发挥作用，这可能会加剧功能获得性 GABRD 变异患者的症状。这也表明在更广泛的神经发育障碍患者中观察到突触外受体过度活跃的现象，因为 SLC6A1 功能丧失变异体也导致过度活跃的含突触外 δ GABAA 受体。这些发现在选择潜在治疗方案时具有重要意义，因为大部分可用的抗癫痫药物通过直接或间接增强 GABA 能功能发挥作用，这可能会加剧功能获得性 GABRD 变异患者的症状。