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

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.

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Publication Details

Journal
npj Genomic Medicine
Published
2025-08-26
DOI
https://doi.org/10.1038/s41525-025-00521-4
Citations
2
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
3.63

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article

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

Tomohide Goto, Dorit Lev, Kosuke Otsuka, Kenji Sugai et al.
2 citations
npj Genomic Medicine
Genomics and Rare Diseases
3.63
article

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

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

Abstract

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.

npj Genomic MedicineVol. 10(1)
Kurume University (JP), SHOWA Medical University (JP), Sapporo Medical University (JP), Jichi Medical University (JP), Asahikawa Medical University (JP), Chiba University (JP), Shiga University of Medical Science (JP), Tel Aviv University (IL), Shiga University (JP), Hokkaido University (JP), Tel Aviv Sourasky Medical Center (IL), Wolfson Medical Center (IL), Yokohama City University Medical Center (JP), Juntendo University (JP), Tsuchiura Kyodo General Hospital (JP), Seirei Mikatabara General Hospital (JP), National Center for Global Health and Medicine (JP), Osaka Women's and Children's Hospital (JP), Saitama Children's Medical Center (JP), Osaka City General Hospital (JP), Yokohama City University Hospital (JP), National Center of Neurology and Psychiatry (JP), Schneider Children's Medical Center (IL), Kanagawa Children's Medical Center (JP), Sapporo Minami Hospital (JP), Hyogo Prefectural Amagasaki General Medical Center (JP), Tokyo Women's Medical University (JP), National Hospital Organization (JP), Hokkaido University Hospital (JP), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Toyohashi Municipal Hospital (JP), Nishi Niigata Chuo National Hospital (JP), Tokyo Women's Medical University Yachiyo Medical Center, The University of Tokyo (JP), Yokohama City University (JP), Tokushima University (JP)
Takeda Science Foundation, Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science
Quality Education
Openalex Percentile: Top 7%
Genomics and Rare Diseases
3.63
DOIOpen Access PDFOpenAlex
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