講演情報
[PE4-6]Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy
○坂本 正宗1, 土田 奈緒美1,2, 内山 由理1,2, 輿水 江里子1, 藤田 京志1, 濱中 耕平1, 三澤 計治1, 宮武 聡子1,3, 水口 剛1, 三宅 紀子1,4, 松本 直通1 (1.横浜市立大学 大学院医学研究科 遺伝学, 2.横浜市立大学附属病院難病ゲノム診断科, 3.横浜市立大学附属病院遺伝子診療科, 4.国立国際医療研究センター疾患ゲノム研究部)
[Purpose] Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, though few comprehensive genetic studies have been reported. [Methods] Using exome sequencing, patients with CBHA in 176 families were genetically examined and patients who have disease-causing variants were clinically evaluated. [Results] In 95 of the 176 families (54%), disease-causing variants were identified. After excluding six families unsuitable for further analysis, 47 patients from 41 families were categorized as having specific diseases associated with CBHA, while the remaining 51 patients from 48 families had true CBHA with and without supratentorial lesions (CBHA+S [N = 15] and CBHA-S [N = 36], respectively). In the 48 families, 26 aberrant genes were identified, of which 20 (76.9%) caused disease in a single family each, with long tail distribution. CACNA1A, ITPR1, and KIF1A were the most prevalent genes (8+8+6=22, 45.8%). Of the 26 aberrant genes, 14 were functionally annotated to cerebellar atrophy. CBHA-S was more clinically milder than CBHA+S. Notably, ARG1 and FOLR1 variants were identified in two families, for whom medical treatments were available. [Conclusion] This cohort revealed a wide genetic and clinical diversity of CBHA by exome sequencing, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was possible for two families.