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Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct

European Journal of Human Genetics (2024)Cite this article

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Abstract

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.

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Fig. 1: Neuropathological and X-Rays skeletal findings in fetus 1 and fetus 3C.

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Data availability

All data generated or analyzed during this study are included in the published article (and its supplementary information files). The genetic variations identified there are already present in ClinVar (ID: 429520, 433156, 7673, cf. Supplementary Fig. 1) and we have submitted them again as pathogenic/likely pathogenic in ClinVar (submission name: SUB14153886, accession numbers: SCV004231896, SCV004231897, SCV004231898).

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Acknowledgements

This research was made possible through access to the data generated by the France Genomic Medicine Plan 2025. We wish to express our sincere gratitude to the parents for their participation.

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Authors and Affiliations

  1. AP-HP, Hôpital Necker-Enfants Malades, Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, Paris, France

    Romain Nicolle, Lucile Boutaud, Laurence Loeuillet, Agnese Feresin, Marie-Paule Beaujard, Férechté Razavi & Tania Attié-Bitach

  2. Université Paris Cité, INSERM UMR 1163, Imagine Institute, Genetics and development of the cerebral cortex, F-75015, Paris, France

    Lucile Boutaud, Nicolas Bourgon, Férechté Razavi & Tania Attié-Bitach

  3. Centre Hospitalier Intercommunal de Créteil, Service d’anatomie pathologique, Université Paris-Est Créteil, 94000, Créteil, France

    Naima Talhi

  4. AP-HP, Hôpital Trousseau, UF de génétique clinique, Centre de Référence anomalies du développement et syndromes malformatifs, Paris, France

    Sarah Grotto

  5. AP-HP, Hôpital Necker-Enfants Malades, Department of Obstetrics and Fetal Medicine, Paris, France

    Nicolas Bourgon

  6. University of Trieste, Department of medicine, Surgery and Health Sciences, Trieste, Italy

    Agnese Feresin

  7. AP-HP, Hôpital Cochin, Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies de Système et d’Organes, Paris, France

    Aurélie Coussement

  8. AP-HP, Hôpital Cochin, Service de Maternité Port-Royal, Paris, France

    Mathilde Barrois

  9. Laboratoire de Biologie Médicale Multi-Sites SeqOIA (laboratoire-seqoia.fr), Paris, France

    Thomas Rambaud & Tania Attié-Bitach

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  1. Romain Nicolle
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Contributions

R.N. and L.B contributed to synthetizing and reviewing data, and writing of the manuscript. L.L., A.F, NT., S.G., N.B., A.C., T.R. and F.R. contributed to generation of data and provided feedback on the manuscript. T.A.B provided project supervision and reviewed the manuscript.

Corresponding author

Correspondence to Tania Attié-Bitach.

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The authors declare no competing interests.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all the parents of the fetuses included in this study.

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Nicolle, R., Boutaud, L., Loeuillet, L. et al. Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01558-2

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