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Novel CLTC variants cause new brain and kidney phenotypes

Journal of Human Genetics volume 67, pages 1–7 (2022)Cite this article

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Abstract

Heterozygous variants in CLTC, which encode the clathrin heavy chain protein, cause neurodevelopmental delay of varying severity, and often accompanied by dysmorphic features, seizures, hypotonia, and ataxia. To date, 28 affected individuals with CLTC variants have been reported, although their phenotypes have not been fully elucidated. Here, we report three novel de novo CLTC (NM_001288653.1) variants in three individuals with previously unreported clinical symptoms: c.3662_3664del:p.(Leu1221del) in individual 1, c.2878T>C:p.(Trp960Arg) in individual 2, and c.2430+1G>T:p.(Glu769_Lys810del) in individual 3. Consistent with previous reports, individuals with missense or small in-frame variants were more severely affected. Unreported symptoms included a brain defect (cystic lesions along the lateral ventricles of the brain in individuals 1 and 3), kidney findings (high-echogenic kidneys in individual 1 and agenesis of the left kidney and right vesicoureteral reflux in individual 3), respiratory abnormality (recurrent pneumonia in individual 1), and abnormal hematological findings (anemia in individual 1 and pancytopenia in individual 3). Of note, individual 1 even exhibited prenatal abnormality (fetal growth restriction, cystic brain lesions, high-echogenic kidneys, and a heart defect), suggesting that CLTC variants should be considered when abnormal prenatal findings in multiple organs are detected.

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Acknowledgements

We thank all the participants in this study. We are grateful to Ms. M. Satoh, Mr. T. Miyama, Ms. K. Takabe, Ms. N. Watanabe, and Ms. S. Sugimoto from the Department of Human Genetics, Yokohama City University Graduate School of Medicine for their technical assistance. This work was supported by the Agency for Medical Research and Development (AMED) under grant numbers JP21ek0109486, JP21ek0109549, JP21cm0106503, and JP21ek0109493 (NM); Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers, JP20K07907 (SM), JP20K08164 (TM), JP20K17936 (AF), JP20K16932 (KH), JP19K17865 (YU), and JP20K17428 (NT); and the Takeda Science Foundation (TM and NM). We thank Rachel James, Ph.D., from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

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

    Toshiyuki Itai, Satoko Miyatake, Naomi Tsuchida, Ken Saida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi & Naomichi Matsumoto

  2. Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa, Japan

    Satoko Miyatake

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

    Naomi Tsuchida & Yuri Uchiyama

  4. Department of Pediatrics, Anjo Kosei Hospital, Anjo, Aichi, Japan

    Sho Narahara

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

    Yu Tsuyusaki

  6. Clinical Genetics Unit, Instituto da Crianca, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

    Matheus Augusto Araujo Castro & Chong Ae Kim

  7. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Japan

    Nobuhiko Okamoto

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  1. Toshiyuki Itai
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Correspondence to Naomichi Matsumoto.

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Itai, T., Miyatake, S., Tsuchida, N. et al. Novel CLTC variants cause new brain and kidney phenotypes. J Hum Genet 67, 1–7 (2022). https://doi.org/10.1038/s10038-021-00957-3

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