Supplementary Material for: Extensive, 3,8 Mb sized deletion of 22q12 in a patient with bilateral schwannoma, intellectual disability, sensorineural hearing loss and epilepsy

Introduction: In contrast with the well-known and described deletion of the 22q11 chromosome region responsible for DiGeorge syndrome, 22q12 deletions are much rarer. Only a few dozen cases have been reported so far. This region contains genes responsible for cell cycle control, chromatin modification, transmembrane signaling, cell adhesion and neural development, as well as several cancer predisposition genes. Case presentation: We present a patient with cleft palate, sensorineural hearing loss, vestibular dysfunction, epilepsy, mild to moderate intellectual disability , divergent strabism, pes equinovarus, platyspondylia, and bilateral Schwannoma. Using Microarray-based Comparative Genomic Hybridization (aCGH), we identified the de novo 3,8 Mb interstitial deletion at 22q12.1→22q12.3. We confirmed deletion of the critical NF2 region by MLPA analysis. Discussion/Conclusion: Large 22q12 deletion in the proband encases the critical NF2 region, responsible for development of bilateral Schwannoma. We compared the phenotype of the patient with previously reported cases. Interestingly, our patient developed cleft palate even without deletion of the MN1 gene, deemed responsible in previous studies. We also strongly suspect the DEPDC5 gene deletion to be responsible for seizures, consistent with previously reported cases.

引言：相较于已被广泛研究与报道的、可引发迪格奥尔格综合征（DiGeorge syndrome）的22q11染色体区域缺失，22q12区域缺失的发病率要低得多。截至目前，全球仅报道了数十例此类病例。该区域包含调控细胞周期、染色质修饰、跨膜信号转导、细胞黏附与神经发育的相关基因，以及多个癌症易感基因。病例报告：本文报道1例合并腭裂、感音神经性听力损失、前庭功能障碍、癫痫、轻中度智力障碍、外斜视（divergent strabism）、马蹄内翻足（pes equinovarus）、扁平椎（platyspondylia）及双侧神经鞘瘤（Schwannoma）的患者。研究人员通过基于微阵列的比较基因组杂交（Microarray-based Comparative Genomic Hybridization, aCGH）技术，检测到该患者存在新发的3.8 Mb间期缺失，缺失区域为22q12.1→22q12.3。随后通过多重连接依赖性探针扩增（MLPA）验证了关键NF2区域的缺失。讨论与结论：先证者的大片段22q12缺失涵盖了与双侧神经鞘瘤发病相关的关键NF2基因区域。研究团队将该患者的表型与既往报道的病例进行了对比分析。值得注意的是，尽管未缺失既往研究认为与腭裂发生相关的MN1基因，本病例仍出现了腭裂表型。此外，研究团队高度怀疑DEPDC5基因的缺失与癫痫发作存在关联，这一结论与既往报道的病例结果一致。