Morato Torres C Alejandra, Zafar Faria, Tsai Yu-Chih, Vazquez Jocelyn Palafox, Gallagher Michael D, McLaughlin Ian, Hong Karl, Lai Jill, Lee Joyce, Chirino-Perez Amanda, Romero-Molina Angel Omar, Torres Francisco, Fernandez-Ruiz Juan, Ashizawa Tetsuo, Ziegle Janet, Jiménez Gil Francisco Javier, Schüle Birgitt
Department Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Pacific Biosciences of California, Inc., Menlo Park, CA 94025, USA.
HGG Adv. 2022 Aug 15;3(4):100137. doi: 10.1016/j.xhgg.2022.100137. eCollection 2022 Oct 13.
Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the gene. This repeat expansion, when fully penetrant, has a size of 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT) and mixed (ATTCT)-(ATTCC) expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with expansions with RNAScope hybridization. All affected family members with the mixed repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT) expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC), are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (), SCA37 (, and three loci for benign adult familial myoclonic epilepsy BAFME (, , ). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.
10型脊髓小脑共济失调（SCA10）是一种常染色体显性疾病，由该基因中的五核苷酸重复序列扩增引起。当这种重复序列扩增完全显性时，其大小为850 - 4500个重复单元。研究表明，重复序列的组成可能是疾病的一个修饰因素，例如癫痫发作。在此，我们描述了一个墨西哥家族，在这个家族中我们在同一家庭中鉴定出了纯合（ATTCT）和混合（ATTCT）-（ATTCC）扩增。我们使用无扩增靶向测序和光学基因组图谱来解读这些重复序列扩增的组成。我们发现重复序列扩增存在相当程度的嵌合现象。通过RNAScope杂交在具有扩增的个体的皮肤成纤维细胞中证实了这种嵌合现象。所有具有混合重复序列扩增的受影响家庭成员均表现出脊髓小脑共济失调和癫痫的典型临床症状。相比之下，具有纯合扩增的个体患有帕金森病或未受影响，即使是那些比SCA10平均发病年龄大20多岁的个体。我们的研究结果表明，纯合（ATTCT）扩增是非致病性的，而重复序列中断，例如（ATTCC），是导致SCA10所必需的。最近在包括SCA31（）、SCA37（）以及良性成人家族性肌阵挛性癫痫BAFME的三个位点（，，）等其他几种重复序列扩增中也描述了这种机制。因此，对重复序列扩增的整个基因组结构进行长读长测序和光学基因组图谱分析对于临床实践和遗传咨询至关重要，因为重复序列的变异会影响疾病的显性率、症状和疾病进程。
