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Developmental defects
Original research
Loss-of-function variants in ZEB1 cause dominant anomalies of the corpus callosum with favourable cognitive prognosis
  1. Solveig Heide1,
  2. Emanuela Argilli2,3,
  3. Stéphanie Valence4,
  4. Lucile Boutaud5,
  5. Nathalie Roux5,
  6. Cyril Mignot1,
  7. Caroline Nava6,
  8. Boris Keren6,
  9. Kim Giraudat4,
  10. Anne Faudet1,
  11. Anna Gerasimenko1,
  12. Catherine Garel7,
  13. Eleonore Blondiaux7,
  14. Agnès Rastetter8,
  15. David Grevent9,10,
  16. Carolyn Le3,11,
  17. Lisa Mackenzie12,
  18. Linda Richards12,13,
  19. Tania Attié-Bitach5,
  20. Christel Depienne14,
  21. Elliott Sherr2,3,
  22. Delphine Héron1
  1. 1 Department of Genetics and Referral Center for Intellectual disabilities of rare causes, AP-HP.Sorbonne Université, Assistance Publique-Hopitaux de Paris, Pitié-Salpêtrière Hospital, Paris, 75013, France, Paris, France
  2. 2 Department of Neurology, University of California San Francisco Division of Hospital Medicine, San Francisco, California, USA
  3. 3 Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, California, USA
  4. 4 Department of Neuropediatry & Referral Center for Intellectual disabilities of rare causes, AP-HP.Sorbonne Université, Hopital Armand-Trousseau, Paris, France
  5. 5 Genomic medicine of rare diseases, UF MP5, Hopital universitaire Necker-enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
  6. 6 Department of Genetics, Unit of Developmental Genomics, AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France
  7. 7 Department of pediatric and prenatal imaging, Armand-Trousseau Hospital, Sorbonne Université, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
  8. 8 Paris Brain Institute (ICM Institut du Cerveau), Sorbonne Université, INSERM UMR S 1127, Paris, France
  9. 9 Radiology Department, Hopital universitaire Necker-enfants Malades, Paris, France
  10. 10 EA fetus 7328 and LUMIERE Platform, Université de Paris, Paris, France
  11. 11 Department of Neurology, University of California, Institute of Human Genetics and Weill Institute for Neurosciences, San Francisco, California, USA
  12. 12 Department of Neuroscience, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
  13. 13 Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
  14. 14 Institute of Human Genetics, University Hospital Essen, Universitu Duisburg-Essen, Essen, Germany
  1. Correspondence to Dr Solveig Heide, AP-HP.Sorbonne Université, Department of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; solveig.heide{at}aphp.fr

Abstract

Background The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered.

Methods Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing.

Results In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1.

Conclusion This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.

  • Genetics, Medical
  • Neurology
  • Nervous System Malformations

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2023-109293

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • SH and EA contributed equally.

    • Contributors SH and EA contributed equally. SH is the guarantor of this study. Analysis and interpretation of data and drafting/revising the manuscript—SH, EA, DH and CD. Study concept and design, acquisition, analysis and interpretation of data, study supervision and coordination, and revising the manuscript—DH, CD and ES. Acquisition of data and revising the manuscript—SV, LB, NR, CM, CN, BK, KG, AF, AG, CG, EB, AR, DG, LM, LR, TA-B and CL.

    • Funding This work was supported by an NIH grant (R01NS058721).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.