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Complete loss of IFT27 function leads to a phenotypic spectrum of fetal lethal ciliopathy associated with altered ciliogenesis

European Journal of Human Genetics volume 33, pages 387–392 (2025)Cite this article

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Abstract

Ciliopathies are rare genetic diseases marked by considerable phenotypic heterogeneity and overlap. Among the key mechanisms of cilium biology, its compartmentalization is achieved through gating complexes and active transport such as intraflagellar transport (IFT). Among the IFT components, IFT27 plays a role in BBSome-mediated transport of ciliary membrane proteins required for ciliary signaling. While this gene was first linked to Bardet-Biedl syndrome, we next expanded its phenotypic spectrum to a fetal lethal ciliopathy. Here, we identified a second fetal case with short ribs, polydactyly, hypodysplastic kidneys, imperforate anus, and situs inversus. Genome sequencing identified novel biallelic variants in IFT27. Functional analysis of tissues from both fetal cases revealed that all the identified variants lead to mRNA decay. Immunohistochemistry on fetal kidney sections showed that those variants are associated with altered ciliogenesis. Overall, we showed that complete loss of IFT27 function leads to a severe phenotypic spectrum overlapping with short ribs polydactyly and Pallister-Hall syndromes. In addition, our results argue for a role of IFT27 in ciliogenesis in humans.

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Fig. 1: Pedigree and phenotypic analysis of the affected fetus.
Fig. 2: Complete loss of IFT27 expression is associated with severely altered ciliogenesis.

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Data availability

The datasets generated during the current study are available in the ClinVar repository, https://www.ncbi.nlm.nih.gov/clinvar/; VCV000591265.5 and VCV001069785.5.

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Acknowledgements

The authors are grateful to the families involved in this study and would like to thank the French Society of Fetal Pathology (SOFFOET).

Funding

This work was supported by grants from the “Agence Nationale de la Recherche” (ANR) to S.T. (ANR-17-CE16-0003-01). The Imagine Institute is funded by the ANR under the “Investissements d’Avenir” program (ANR-10-IAHU-01) and as part of the second “Investissements d’Avenir” program (ANR-17-RHUS-0002).

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Authors and Affiliations

  1. Consultations d’Échographies Prénatales, Centre Hospitalier de Roubaix, Roubaix, France

    David Haïm

  2. Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Assistance Publique—Hôpitaux de Paris (AP-HP), Paris, France

    Nathalie Roux, Lucile Boutaud, Amale Achaiia & Tania Attié-Bitach

  3. INSERM UMR-1163, Institut Imagine, Université Paris Cité, Paris, France

    Lucile Boutaud, Laure Verlin, Candice Moncler, Nicolas Bourgon, Sophie Thomas & Tania Attié-Bitach

  4. Laboratoire de Biologie Médicale Multisites SeqOIA, Paris, France

    Lucile Boutaud, Pierre Marijon & Tania Attié-Bitach

  5. Département de Génétique Moléculaire et Génomique, CHU Rennes, Rennes, France

    Chloé Quélin

  6. Service d’Obstétrique – Maternité, Chirurgie, Médecine et Imagerie Fœtales, Hôpital Necker—Enfants Malades, AP-HP Centre, Paris, France

    Nicolas Bourgon & Philippe Roth

  7. Hôpital Foch, Suresnes, France

    Sarah Vanlieferinghen

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  1. David Haïm
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  2. Nathalie Roux
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  11. Sarah Vanlieferinghen
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  12. Sophie Thomas
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  13. Tania Attié-Bitach
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Contributions

Study conception: TAB; data acquisition: all authors; manuscript drafting: DH, ST, TAB; manuscript revision, editing, and approval: all authors.

Corresponding authors

Correspondence to Sophie Thomas or Tania Attié-Bitach.

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Competing interests

The authors declare no competing interests.

Ethical approval

Medical terminations of pregnancy were performed in accordance with French law and with approval from our local committee. Autopsies were conducted after informing and obtaining written consent from the parents. The parents also provided informed consent for genetic testing, and the study was approved by the ethical committee of Paris Ile-de-France II.

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Haïm, D., Roux, N., Boutaud, L. et al. Complete loss of IFT27 function leads to a phenotypic spectrum of fetal lethal ciliopathy associated with altered ciliogenesis. Eur J Hum Genet 33, 387–392 (2025). https://doi.org/10.1038/s41431-025-01810-3

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