講演情報
[O23-2]NOTCH2NLCの両アレル性GGCリピート伸長を有する患者は典型的な神経核内封入体病の表現型を呈する
○亀山 真一1,2, 水口 剛1, 土井 宏3, 児矢野 繁4, 大久保 正紀3, 多田 美紀子3, 清水 宏5, 福田 裕美1,3, 土田 奈緒美1,6, 内山 由理1,6, 輿水 江里子1, 濱中 耕平1, 藤田 京志1, 三澤 計治1, 宮武 聡子1,7, 金井 数明8, 田中 章景3, 松本 直通1 (1.横浜市立大学大学院 医学研究科 遺伝学, 2.慶應義塾大学 医学部 病理学教室, 3.横浜市立大学 大学院医学研究科 神経内科学・脳卒中医学, 4.国家公務員共済組合連合会 横浜南共済病院 脳神経内科, 5.新潟大学 脳研究所 病理学分野, 6.横浜市立大学附属病院 難病ゲノム診療科, 7.横浜市立大学附属病院 遺伝子診療科, 8.福島県立医科大学 医学部 脳神経内科学講座)
The genotype-phenotype correlation of NOTCH2NLC-related diseases may be attributed to multiple factors such as repeat lengths, epigenetic modification, and repeat motifs. However, the relationship between repeat expansion zygosity and clinical phenotype has not been fully elucidated. Here we report two patients with neuronal intranuclear inclusion disease (NIID) with the biallelic GGC repeat expansion in NOTCH2NLC to uncover the impact of repeat expansion zygosity on the clinical phenotype of NOTCH2NLC-related diseases. We recruited two Japanese patients clinically diagnosed with NIID. In fluorescent amplicon length PCR, we observed amplicons suggestive of only repeat expansion alleles but not those of the wild-type allele, which indicated the presence of the biallelic repeat expansion in NOTCH2NLC. PacBio targeted long-read sequencing revealed that one patient harbored almost the same expanded allele containing GGC repeats in NOTCH2NLC without a non-expanded allele, which suggested homozygous repeat expansion. The other patient harbored two expanded alleles with different lengths of GGC repeats, which suggested compound heterozygous repeat expansion. Nanopore long-read DNA methylation analysis revealed that the GGC repeats and the nearest CpG island were hypomethylated in all expanded alleles in both patients. Both patients harboring the biallelic GGC repeat expansion showed a typical dementia-dominant NIID phenotype. In summary, the biallelic repeat expansion in two typical NIID patients indicated that NOTCH2NLC-related diseases can be completely dominant.