Presentation Information
[PE4-6]Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy
○Masamune Sakamoto1, Naomi Tsuchida1,2, Yuri Uchiyama1,2, Eriko Koshimizu1, Atsushi Fujita1, Kouhei Hamanaka1, Kazuharu Misawa1, Satoko Miyatake1,3, Takeshi Mizuguchi1, Noriko Miyake1,4, Naomichi Matsumoto1 (1.Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan, 2.Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan, 3.Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan, 4.Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan)
[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.