Hamanaka Kohei, Fujita Atsushi, Miyatake Satoko, Misawa Kazuharu, Koshimizu Eriko, Uchiyama Yuri, Tsuchida Naomi, Seyama Rie, Sakamoto Masamune, Iwama Kazuhiro, Nishimura Naoto, Utsuno Yasuhiro, Fu Li, Takizawa Marina, Liang Qiaowei, Itai Toshiyuki, Saida Ken, Ohori Sachiko, Kameyama Shinichi, Fukuda Hiromi, Hayashi Yukina, Inoue Yuta, Goto Tomohide, Ichikawa Kazushi, Kuki Ichiro, Fukuoka Masataka, Kim Kiyohiro, Shiohama Tadashi, Shimoda Konomi, Otsuka Kosuke, Ueda Yuki, Cho Kazutoshi, Yuge Kotaro, Tachi Nobutada, Yoshida Masaki, Daida Atsuro, Hirasawa Kyoko, Yanagishita Tomoe, Yamamoto Toshiyuki, Shirai Kentaro, Mehr Tammar Fixler, Fattal-Valevski Aviva, Lev Dorit, Yokoyama Haruna, Iwabuchi Emi, Saito Yoshihiko, Miura Masaki, Sugai Kenji, Ishiyama Akihiko, Sasaki Masayuki, Watanabe Yoshihiro, Takanashi Jun-Ichi, Kim Chong Ae, Yokochi Kenji, Tohyama Jun, Mori Tatsuo, Izumi Yuishin, Hasegawa Yuiko, Okamoto Nobuhiko, Ikeda Takahiro, Osaka Hitoshi, Kawai Yosuke, Omae Yosuke, Tokunaga Katsushi, Kato Mitsuhiro, Mizuguchi Takeshi, Matsumoto Naomichi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Kanagawa, Japan.
NPJ Genom Med. 2025 Aug 26;10(1):60. doi: 10.1038/s41525-025-00521-4.
Short-read genome sequencing (GS) is a powerful technique for investigating the genetic etiologies of rare diseases, capturing diverse genetic variations that are challenging to approach with exome sequencing (ES). We performed GS on 260 families with intellectual disability/developmental delay. GS detected potentially disease-related variants in 55 of the 260 families, with structural resolution by long-read sequencing or optical genome mapping, and functional assessment by RNA sequencing. Excluding 31 theoretically ES-resolvable cases, GS yielded likely pathogenic variants in 17 of 229 as well as variants of unknown significance in 7 of 229, totaling 10.5%. These variants implicated several new etiological mechanisms: a microduplication syndrome involving ATP6V0C; disturbed interactions of TBL1XR1 and NR2F1 with putative cis-regulatory elements by chromosomal rearrangements; and a CCG repeat expansion near the CHD3 transcription start site. This study highlights the critical role of GS in clinical diagnostics and its potential to advance understanding of genetic disorders.
短读长基因组测序（GS）是一种用于研究罕见病遗传病因的强大技术，它能够捕捉各种难以通过外显子组测序（ES）检测到的遗传变异。我们对260个患有智力残疾/发育迟缓的家庭进行了GS检测。GS在260个家庭中的55个家庭中检测到了潜在的疾病相关变异，并通过长读长测序或光学基因组图谱进行结构解析，通过RNA测序进行功能评估。排除31个理论上可通过ES解决的病例后，GS在229个家庭中的17个家庭中产生了可能致病的变异，在229个家庭中的7个家庭中产生了意义不明的变异，总计占10.5%。这些变异涉及几种新的致病机制：一种涉及ATP6V0C的微重复综合征；TBL1XR1和NR2F1通过染色体重排与假定的顺式调控元件的相互作用受到干扰；以及CHD3转录起始位点附近的CCG重复序列扩增。这项研究突出了GS在临床诊断中的关键作用及其推进对遗传疾病理解的潜力。
