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Biallelic TXNDC15 variants associated with Joubert syndrome-related molar tooth sign and forebrain malformation

Journal of Human Genetics volume 70, pages 59–62 (2025)Cite this article

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Abstract

TXNDC15 encodes thioredoxin domain-containing protein 15, a protein disulfide isomerase that plays a role in ciliogenesis. Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes, but have not been reported in patients with Joubert syndrome (JS). Here, we describe a 1-year-old female patient with compound heterozygous TXNDC15 variants demonstrating cerebellar vermis hypoplasia with the molar tooth sign, mild holoprosencephaly, and cortical abnormalities. She had severe developmental delay and epilepsy. Her clinical features were similar to those of JS, but distinctive forebrain abnormalities were also noted including mild holoprosencephaly and cortical abnormalities, which have been reported in a severe form of ciliopathy. Biallelic TXNDC15 variants manifest as overlapping phenotypes of JS and MKS, including the molar tooth sign, cortical dysgenesis, and mild holoprosencephaly. This report supports the hypothesis that JS and MKS are spectrum ciliopathy disorders with overlapping causative genes and hypomorphic TXNDC15 variants might contribute to JS.

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Fig. 1

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Shaheen R, Szymanska K, Basu B, Patel N, Ewida N, Faqeih E, et al. Characterizing the morbid genome of ciliopathies. Genome Biol. 2016;17:242.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ridnõi K, Šois M, Vaidla E, Pajusalu S, Kelder L, Reimand T, et al. A prenatally diagnosed case of Meckel-Gruber syndrome with novel compound heterozygous pathogenic variants in the TXNDC15 gene. Mol Genet Genom Med. 2019;7:e614.

    Article  Google Scholar 

  3. Deng T, Xie Y. Novel homozygous mutations in TXNDC15 causing Meckel syndrome. Mol Genet Genom Med. 2024;12:e2343.

    Article  CAS  Google Scholar 

  4. Radhakrishnan P, Nayak SS, Shukla A, Lindstrand A, Girisha KM. Meckel syndrome: clinical and mutation profile in six fetuses. Clin Genet. 2019;96:560–65.

    Article  CAS  PubMed  Google Scholar 

  5. Andreu-Cervera A, Catala M, Schneider-Maunoury S. Cilia, ciliopathies and hedgehog-related forebrain developmental disorders. Neurobiol Dis. 2021;150:105236.

    Article  CAS  PubMed  Google Scholar 

  6. Gleeson JG, Keeler LC, Parisi MA, Marsh SE, Chance PF, Glass IA, et al. Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes. Am J Med Genet A. 2004;125A:125–34.

    Article  PubMed  Google Scholar 

  7. Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet. 2004;75:979–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Giordano L, Vignoli A, Pinelli L, Brancati F, Accorsi P, Faravelli F, et al. Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers. Am J Med Genet A. 2009;149A:1511–5.

    Article  CAS  PubMed  Google Scholar 

  9. Poretti A, Snow J, Summers AC, Tekes A, Huisman TAGM, Aygun N, et al. Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause. J Med Genet. 2017;54:521–29.

    Article  CAS  PubMed  Google Scholar 

  10. Van De Weghe JC, Rusterholz TDS, Latour B, Grout ME, Aldinger KA, Shaheen R, et al. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome in humans and ciliopathy phenotypes in zebrafish. Am J Hum Genet. 2017;101:23–36.

    Article  PubMed  Google Scholar 

  11. Ahdab-Barmada M, Claassen D. A distinctive triad of malformations of the central nervous system in the Meckel-Gruber syndrome. J Neuropathol Exp Neurol. 1990;49:610–20.

    Article  CAS  PubMed  Google Scholar 

  12. Stottmann RW, Tran PV, Turbe-Doan A, Beier DR. Ttc21b is required to restrict sonic hedgehog activity in the developing mouse forebrain. Dev Biol. 2009;335:166–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gorivodsky M, Mukhopadhyay M, Wilsch-Braeuninger M, Phillips M, Teufel A, Kim C, et al. Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain. Dev Biol. 2009;325:24–32.

    Article  CAS  PubMed  Google Scholar 

  14. Besse L, Neti M, Anselme I, Gerhardt C, Rüther U, Laclef C, et al. Primary cilia control telencephalic patterning and morphogenesis via Gli3 proteolytic processing. Development. 2011;138:2079–88.

    Article  CAS  PubMed  Google Scholar 

  15. Mariani LE, Bijlsma MF, Ivanova AA, Suciu SK, Kahn RA, Caspary T. Arl13b regulates Shh signaling from both inside and outside the cilium. Mol Biol Cell. 2016;27:3780–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Van De Weghe JC, Giordano JL, Mathijssen IB, Mojarrad M, Lugtenberg D, Miller CV, et al. TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes. HGG Adv. 2021;2:100016.

    PubMed  Google Scholar 

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Funding

This study was supported by The Initiative on Rare and Undiagnosed Diseases (grant number 23ek0109549) from the Japan Agency for Medical Research and Development, MHLW Health Labour Sciences Research Grant (number 23FC1052), and JSPS KAKENHI Grant (number 23K14966 to YK). We thank the patient and her family for their cooperation.

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Authors and Affiliations

  1. Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

    Yukiko Kuroda & Kenji Kurosawa

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

    Tamaki Ikegawa

  3. Division of Radiology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Ayumi Kato & Noriko Aida

  4. Department of Diagnostic Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Ayumi Kato & Noriko Aida

  5. Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan

    Takuya Naruto

Authors
  1. Yukiko Kuroda
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  2. Tamaki Ikegawa
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  3. Ayumi Kato
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  4. Noriko Aida
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  5. Takuya Naruto
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  6. Kenji Kurosawa
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Contributions

Kenji Kurosawa designed the study. Takuya Naruto performed the bioinformatics experiments and contributed to the genetics experiments. Yukiko Kuroda, Tamaki Ikegawa, Ayumi Kato, and Noriko Aida recruited and evaluated the study subjects. Kenji Kurosawa supervised Yukiko Kuroda. Yukiko Kuroda wrote the manuscript.

Corresponding authors

Correspondence to Yukiko Kuroda or Kenji Kurosawa.

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The authors declare no competing interests.

Ethical approval

The patient and family members were enrolled in an institutional review board-approved study with informed consent at Kanagawa Children’s Medical Center. Written informed consent for the publication of images was obtained.

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Kuroda, Y., Ikegawa, T., Kato, A. et al. Biallelic TXNDC15 variants associated with Joubert syndrome-related molar tooth sign and forebrain malformation. J Hum Genet 70, 59–62 (2025). https://doi.org/10.1038/s10038-024-01290-1

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  • DOI: https://doi.org/10.1038/s10038-024-01290-1

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