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Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies

Journal of Human Genetics volume 66, pages 1061–1068 (2021)Cite this article

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Abstract

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.

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The data that support the findings of this study are available in the supplementary material of this article.

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Acknowledgements

The authors would like to thank the patient’s family for participating in this study. The authors also thank K. Shibazaki, M. Tsujimura, and A. Kitamoto for their technical assistance. This study was supported by Grant‐in‐Aid from the Ministry of Health, Labour and Welfare of Japan, the Takeda Science Foundation, and HUSM Grant-in-Aid from Hamamatsu University School of Medicine.

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Authors and Affiliations

  1. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Sachiko Miyamoto, Takuya Hiraide, Mitsuko Nakashima & Hirotomo Saitsu

  2. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    Mitsuhiro Kato, Akira Hojo, Akio Ebata, Manabu Suzuki & Kozue Kobayashi

  3. Department of Pediatrics, Graduated School of Medicine, Chiba University, Chiba, Japan

    Tadashi Shiohama

  4. Division of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Tomohide Goto

  5. Department of Pediatric Neurology, Fukuoka Children’s Hospital, Fukuoka, Japan

    Pin Fee Chong & Ryutaro Kira

  6. Department of Pediatrics, Kyoto Kuramaguchi Medical Center, Kyoto, Japan

    Hiroko Baber Matsushita

  7. Department of Pediatrics, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan

    Hiroko Ikeda

  8. Segawa Memorial Neurological Clinic for Children, Tokyo, Japan

    Kyoko Hoshino

  9. Department of Pediatrics, Minami Kyushu National Hospital, Aira, Japan

    Mayumi Matsufuji

  10. Department of Pediatrics, Hitachi, Ltd., Hitachinaka General Hospital, Hitachinaka, Japan

    Nobuko Moriyama

  11. Department of Pediatrics, Okitama Public General Hospital, Yamagata, Japan

    Masayuki Furuyama

  12. Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan

    Tatsuya Yamamoto

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  1. Sachiko Miyamoto
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Correspondence to Mitsuko Nakashima or Hirotomo Saitsu.

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Miyamoto, S., Kato, M., Hiraide, T. et al. Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies. J Hum Genet 66, 1061–1068 (2021). https://doi.org/10.1038/s10038-021-00932-y

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