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<p>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 <i>ATP6V0C</i>; disturbed interactions of <i>TBL1XR1</i> and <i>NR2F1</i> with putative cis-regulatory elements by chromosomal rearrangements; and a CCG repeat expansion near the <i>CHD3</i> transcription start site. This study highlights the critical role of GS in clinical diagnostics and its potential to advance understanding of genetic disorders.</p>

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Genome sequencing provides high diagnostic yield and new etiological insights for intellectual disability and developmental delay

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Kohei Hamanaka,
  • Atsushi Fujita,
  • Satoko Miyatake,
  • Kazuharu Misawa,
  • Eriko Koshimizu,
  • Yuri Uchiyama,
  • Naomi Tsuchida,
  • Rie Seyama,
  • Masamune Sakamoto,
  • Kazuhiro Iwama,
  • Naoto Nishimura,
  • Yasuhiro Utsuno,
  • Li Fu,
  • Marina Takizawa,
  • Qiaowei Liang,
  • Toshiyuki Itai,
  • Ken Saida,
  • Sachiko Ohori,
  • Shinichi Kameyama,
  • Hiromi Fukuda,
  • Yukina Hayashi,
  • Yuta Inoue,
  • Tomohide Goto,
  • Kazushi Ichikawa,
  • Ichiro Kuki,
  • Masataka Fukuoka,
  • Kiyohiro Kim,
  • Tadashi Shiohama,
  • Konomi Shimoda,
  • Kosuke Otsuka,
  • Yuki Ueda,
  • Kazutoshi Cho,
  • Kotaro Yuge,
  • Nobutada Tachi,
  • Masaki Yoshida,
  • Atsuro Daida,
  • Kyoko Hirasawa,
  • Tomoe Yanagishita,
  • Toshiyuki Yamamoto,
  • Kentaro Shirai,
  • Tammar Fixler Mehr,
  • Aviva Fattal-Valevski,
  • Dorit Lev,
  • Haruna Yokoyama,
  • Emi Iwabuchi,
  • Yoshihiko Saito,
  • Masaki Miura,
  • Kenji Sugai,
  • Akihiko Ishiyama,
  • Masayuki Sasaki,
  • Yoshihiro Watanabe,
  • Jun-ichi Takanashi,
  • Chong Ae Kim,
  • Kenji Yokochi,
  • Jun Tohyama,
  • Tatsuo Mori,
  • Yuishin Izumi,
  • Yuiko Hasegawa,
  • Nobuhiko Okamoto,
  • Takahiro Ikeda,
  • Hitoshi Osaka,
  • Yosuke Kawai,
  • Yosuke Omae,
  • Katsushi Tokunaga,
  • Mitsuhiro Kato,
  • Takeshi Mizuguchi,
  • Naomichi Matsumoto

摘要

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.