Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy

Masamune Sakamoto, Kazuhiro Iwama, Masayuki Sasaki, Akihiko Ishiyama, Hirofumi Komaki, Takashi Saito, Eri Takeshita, Yuko Shimizu-Motohashi, Kazuhiro Haginoya, Tomoko Kobayashi, Tomohide Goto, Yu Tsuyusaki, Mizue Iai, Kenji Kurosawa, Hitoshi Osaka, Jun Tohyama, Yu Kobayashi, Nobuhiko Okamoto, Yume Suzuki, Satoko KumadaKenji Inoue, Hideaki Mashimo, Atsuko Arisaka, Ichiro Kuki, Harumi Saijo, Kenji Yokochi, Mitsuhiro Kato, Yuji Inaba, Yuko Gomi, Shinji Saitoh, Kentaro Shirai, Masafumi Morimoto, Yuishin Izumi, Yoriko Watanabe, Shin ichiro Nagamitsu, Yasunari Sakai, Shinobu Fukumura, Kazuhiro Muramatsu, Tomomi Ogata, Keitaro Yamada, Keiko Ishigaki, Kyoko Hirasawa, Konomi Shimoda, Manami Akasaka, Kosuke Kohashi, Takafumi Sakakibara, Masashi Ikuno, Noriko Sugino, Takahiro Yonekawa, Semra Gürsoy, Tayfun Cinleti, Chong Ae Kim, Keng Wee Teik, Chan Mei Yan, Muzhirah Haniffa, Chihiro Ohba, Shuuichi Ito, Hirotomo Saitsu, Ken Saida, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Noriko Miyake, Naomichi Matsumoto

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. Methods: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. Results: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA–S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. Conclusion: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Original languageEnglish
Pages (from-to)2453-2463
Number of pages11
JournalGenetics in Medicine
Volume24
Issue number12
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)

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