Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062, Aachen, Germany.
Nat Commun. 2019 Oct 29;10(1):4919. doi: 10.1038/s41467-019-12763-9.
Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
家族性成年肌阵挛性癫痫（FAME）是一种具有皮质震颤和癫痫发作特征的遗传异质性疾病。SAMD12（FAME1）中的内含子 TTTTA/TTTCA 重复扩展是亚洲 FAME 的主要原因。使用基因组测序和重复引物 PCR，我们在四个欧洲家族中鉴定出 MARCH6（FAME3）中的另一个重复扩展位点。用纳米孔测序和分子梳理分析单 DNA 分子表明，扩展平均范围为 3.3 至 14kb。然而，我们观察到扩展长度和结构存在相当大的可变性，支持同一个体的血细胞和成纤维细胞中存在多种扩展构型。此外，最大的扩展与扩展附近 20%的细胞中发生的微重排有关。这项研究进一步证明 FAME 是由不同基因中的内含子 TTTTA/TTTCA 扩展引起的，并揭示了扩展表现出出乎意料的高体细胞不稳定性，最终可能导致基因组重排。
