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Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling

Journal of Human Genetics volume 69, pages 153–157 (2024)Cite this article

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Abstract

Aromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter disorder caused by pathogenic DOPA decarboxylase (DDC) variants. We previously reported Japanese siblings with AADC deficiency, which was confirmed by the lack of enzyme activity; however, only a heterozygous missense variant was detected. We therefore performed targeted long-read sequencing by adaptive sampling to identify any missing variants. Haplotype phasing and variant calling identified a novel deep intronic variant (c.714+255 C > A), which was predicted to potentially activate the noncanonical splicing acceptor site. Minigene assay revealed that wild-type and c.714+255 C > A alleles had different impacts on splicing. Three transcripts, including the canonical transcript, were detected from the wild-type allele, but only the noncanonical cryptic exon was produced from the variant allele, indicating that c.714+255 C > A was pathogenic. Target long-read sequencing may be used to detect hidden pathogenic variants in unresolved autosomal recessive cases with only one disclosed hit variant.

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Acknowledgements

We thank M. Sato, T. Miyama, N. Watanabe, S. Sugimoto, and K. Takabe for technical assistance. We also thank Susan Furness, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP23ek0109674, JP23ek0109549, JP23ek0109617, and JP23ek0109648 (NM); JSPS KAKENHI under grant numbers JP21K07869 (EK), JP20K08236 (MK), JP22K15646 (KH), JP23K07229 (YU), JP23K15353 (NT), JP22K15901 (AF), JP20K07316 (KM), JP23H02829 (SM), and JP23H02877 (TM); and the Takeda Science Foundation (TM and NM).

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Authors and Affiliations

  1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Eriko Koshimizu, Kazuharu Misawa, Yuri Uchiyama, Naomi Tsuchida, Atsushi Fujita, Takeshi Mizuguchi, Satoko Miyatake & Naomichi Matsumoto

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

    Mitsuhiro Kato

  3. RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo, Japan

    Kazuharu Misawa

  4. Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan

    Yuri Uchiyama & Naomi Tsuchida

  5. Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan

    Kohei Hamanaka

  6. Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kohei Hamanaka

  7. Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan

    Satoko Miyatake

Authors
  1. Eriko Koshimizu
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  2. Mitsuhiro Kato
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  3. Kazuharu Misawa
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  4. Yuri Uchiyama
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  5. Naomi Tsuchida
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  6. Kohei Hamanaka
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  7. Atsushi Fujita
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  8. Takeshi Mizuguchi
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  9. Satoko Miyatake
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  10. Naomichi Matsumoto
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Contributions

Conceptualization: EK, MK, SM, NM; investigation: EK, SM, KM, YU, NT, KH, AF, TM; resources: EK, NM; writing—original draft: EK, NM; writing—review and editing: EK, NM. All authors read and approved the final manuscript before submission.

Corresponding authors

Correspondence to Satoko Miyatake or Naomichi Matsumoto.

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The authors declare no competing interests.

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The experimental protocol was approved by the Committee for Ethical Issues at Yokohama City University School of Medicine. Written informed consent was obtained from all individuals.

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Koshimizu, E., Kato, M., Misawa, K. et al. Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling. J Hum Genet 69, 153–157 (2024). https://doi.org/10.1038/s10038-023-01217-2

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  • DOI: https://doi.org/10.1038/s10038-023-01217-2

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