[O15] 一般口演 15　神経遺伝学 3

[O15-1] ExpansionHunter Denovoで検出されたRFC1遺伝子にAAGGGおよびACAGGリピート伸長を持つ家系における認知機能障害

^○渡邊 一樹^1,2, 中島 光子¹, 若月 里江², 武内 智康², 尾内 康臣³, 中村 友彦², 宮嶋 裕明², 才津 浩智¹ (1.浜松医科大学 医化学講座, 2.浜松医科大学 脳神経内科, 3.浜松医科大学 生体機能イメージング研究室)

【Objective】We investigated the genetic basis and brain metabolism and blood flow of a Japanese family with spinocerebellar degeneration, with multiple affected members for three generations.【Methods】We performed whole exome sequencing (WES) and whole genome sequencing (WGS). Homozygosity mapping were performed using these data. Repeat expansions (REs) were investigated with WGS data using ExpansionHunter Denovo and Expansion Hunter. 【Results】WES and WGS were unable to identify likely pathogenic variants, and homozygosity mapping failed to narrow down the locus. However, ExpansionHunter Denovo detected REs in intron 2 of the RFC1 gene and led us to the diagnosis of RFC1-related disorders. Subsequent repeat primed PCR and Southern blot hybridization analyses revealed that four individuals had AAGGG_exp and ACAGG_exp in a compound heterozygous state, and three had a homozygous ACAGG_exp. Cognitive function tests showed cognitive impairment with a predominance of frontal lobe dysfunction. Examination of MRI, SPECT, and 18F-FDG PET showed cortical damage with frontal lobe predominance in one case, but no cerebral damage was evident in the other two cases. 【Conclusions】Our report shows the usefulness of WGS and RE detection tools for spinocerebellar degeneration of unknown cause. One patient presented with cognitive impairment due to frontal lobe metabolic changes, but other two patients presented with cognitive impairment without apparent cerebral metabolic or blood flow, suggesting that other factors are also associated with cognitive impairment.