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Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield

Journal of Human Genetics (2024)Cite this article

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Abstract

Lissencephaly is a rare brain malformation characterized by abnormal neuronal migration during cortical development. In this study, we performed a comprehensive genetic analysis using next-generation sequencing in 12 unsolved Japanese lissencephaly patients, in whom PAFAH1B1, DCX, TUBA1A, and ARX variants were excluded using the Sanger method. Exome sequencing (ES) was conducted on these 12 patients, identifying pathogenic variants in CEP85L, DYNC1H1, LAMC3, and DCX in four patients. Next, we performed genome sequencing (GS) on eight unsolved patients, and structural variants in PAFAH1B1, including an inversion and microdeletions involving several exons, were detected in three patients. Notably, these microdeletions in PAFAH1B1 could not to be detected by copy number variation (CNV) detection tools based on the depth of coverage methods using ES data. The density of repeat sequences, including Alu sequences or segmental duplications, which increase the susceptibility to structural variations, is very high in some lissencephaly spectrum genes (PAFAH1B1, TUBA1A, DYNC1H1). These missing CNVs were due to the limitations of detecting repeat sequences in ES-based CNV detection tools. Our study suggests that a combined approach integrating ES with GS can contribute to a higher diagnostic yield and a better understanding of the genetic landscape of the lissencephaly spectrum.

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Acknowledgements

We thank the patient’s family for their participation in this study. We thank M. Tsujimura, K Shibasaki, M Tanaka, C. Ogawa and A. Kitamoto for their technical assistance. This work was supported in part by the Japan Society for the Promotion of Science, KAKENHI (Grant number JP 20H03641 and 23H02875 (HS), JP20K08236 (MK) and JP21K06819 (MN)), the Japan Agency for Medical Research and Development (AMED) (JP23ek0109549 and 23ek01099674, HS), the Takeda Science Foundation (MN and HS), and HUSM Grant-in-Aid from Hamamatsu University School of Medicine (MN and HS).

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Authors and Affiliations

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

    Shogo Furukawa, Mitsuko Nakashima & Hirotomo Saitsu

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

    Mitsuhiro Kato

  3. Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

    Akihiko Ishiyama & Eri Takeshita

  4. Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Japan

    Tomohiro Kumada

  5. Kumada Kids-Family Clinic, Moriyama, Japan

    Tomohiro Kumada

  6. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takeshi Yoshida

  7. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Pin Fee Chong

  8. Department of Pediatrics, Saitama Medical University, Saitama, Japan

    Hideo Yamanouchi

  9. Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan

    Yuko Kotake

  10. Children’s Medical Center, Showa University Northern Yokohama Hospital, Yokohama, Japan

    Takayoshi Kyoda

  11. Department of Pediatrics, Kawaguchi Municipal Medical Center, Saitama, Japan

    Toshihiro Nomura

  12. Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan

    Yohane Miyata

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  1. Shogo Furukawa
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Correspondence to Hirotomo Saitsu.

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Furukawa, S., Kato, M., Ishiyama, A. et al. Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01283-0

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