Individuals with severe and treatment‐resistant obsessive‐compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS‐treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene‐disruptive rare variants (GDRVs; rare, predicted‐deleterious single‐nucleotide variants or copy number variants overlapping protein‐coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20‐47991077‐C‐T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans‐membrane region of neuronal potassium voltage‐gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.

中文翻译：

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深部脑刺激治疗的严重难治性强迫症的基因组学：初步研究

患有严重且难以治疗的强迫症（trOCD）的个体代表了一小部分但严重残疾的患者群体。由于适合接受深部脑刺激 (DBS) 的 trOCD 病例可能包括 OCD 谱系中最严重的一端，因此我们假设他们的疾病更有可能受到强烈的遗传影响。因此，虽然全球接受 DBS 治疗的病例数量可能很少（约 300 例），但用现代基因组方法筛选这些个体可能会加速强迫症基因的发现。因此，我们已经开始从符合 DBS 资格的 trOCD 病例中收集 DNA，在这里我们报告了前 5 个病例的全外显子组测序和微阵列基因分型的结果。所有参与者之前都接受过终纹床核 (BNST) 的 DBS 治疗，其中两名患者对手术有反应，一名患者显示部分反应。我们的分析重点是基因破坏性罕见变异（GDRV；罕见的、预测有害的单核苷酸变异或与蛋白质编码基因重叠的拷贝数变异）。五个病例中的三个携带 GDRV，包括离子转运蛋白域中的错义变体KCNB1，15q11.2 处的缺失，以及 15q26.1 处的重复。这KCNB1变体（hg19 chr20-47991077-C-T、NM_004975.3:c.1020G>A、p.Met340Ile）导致神经元钾电压门控离子通道 KV2.1 跨膜区域中的蛋氨酸取代异亮氨酸。这KCNB1取代（Met340Ile）位于蛋白质的一个高度受限的区域，其他罕见的错义变异此前已被认为与神经发育障碍有关。携带 Met340Ile 变异的患者对 DBS 有反应，这表明遗传因素可能是 DBS 治疗强迫症治疗反应的潜在预测因素。总之，我们建立了一个招募 trOCD 病例并对其进行基因组表征的方案。初步结果表明，这将是寻找强迫症风险基因的一种信息丰富的策略。