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Developmental defects
Original research
Biallelic truncating variants in VGLL2 cause syngnathia in humans
  1. Valeria Agostini1,
  2. Aude Tessier1,
  3. Nabila Djaziri1,
  4. Roman Hossein Khonsari2,
  5. Eva Galliani2,
  6. Yukiko Kurihara3,
  7. Masahiko Honda4,
  8. Hiroki Kurihara3,
  9. Kyoko Hidaka5,
  10. Gokhan Tuncbilek6,
  11. Arnaud Picard2,
  12. Ersoy Konas6,
  13. Jeanne Amiel1,7,
  14. Christopher T Gordon1
  1. 1 Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine and Université Paris Cité, Paris, France
  2. 2 Service de Chirurgie Maxillofaciale et Chirurgie Plastique, Centre de référence Fentes et Malformations Faciales (MAFACE), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Cité, Paris, France
  3. 3 Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  4. 4 Department of Biochemistry, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
  5. 5 Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
  6. 6 Hacettepe University, Ankara, Turkey
  7. 7 Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  1. Correspondence to Dr Christopher T Gordon, Institut Imagine, Paris 75015, France; chris.gordon{at}inserm.fr; Professor Jeanne Amiel, Institut Imagine, Paris 75015, France; jeanne.amiel{at}inserm.fr

Abstract

Background Syngnathia is an ultrarare craniofacial malformation characterised by an inability to open the mouth due to congenital fusion of the upper and lower jaws. The genetic causes of isolated bony syngnathia are unknown.

Methods We used whole exome and Sanger sequencing and microsatellite analysis in six patients (from four families) presenting with syngnathia. We used CRISPR/Cas9 genome editing to generate vgll2a and vgll4l germline mutant zebrafish, and performed craniofacial cartilage analysis in homozygous mutants.

Results We identified homozygous truncating variants in vestigial-like family member 2 (VGLL2) in all six patients. Two alleles were identified: one in families of Turkish origin and the other in families of Moroccan origin, suggesting a founder effect for each. A shared haplotype was confirmed for the Turkish patients. The VGLL family of genes encode cofactors of TEAD transcriptional regulators. Vgll2 is regionally expressed in the pharyngeal arches of model vertebrate embryos, and morpholino-based knockdown of vgll2a in zebrafish has been reported to cause defects in development of pharyngeal arch cartilages. However, we did not observe craniofacial anomalies in vgll2a or vgll4l homozygous mutant zebrafish nor in fish with double knockout of vgll2a and vgll4l. In Vgll2 −/− mice, which are known to present a skeletal muscle phenotype, we did not identify defects of the craniofacial skeleton.

Conclusion Our results suggest that although loss of VGLL2 leads to a striking jaw phenotype in humans, other vertebrates may have the capacity to compensate for its absence during craniofacial development.

  • congenital, hereditary, and neonatal diseases and abnormalities

Data availability statement

Data are available upon reasonable request. All data that support the findings of this study are available on request from the corresponding authors.

https://doi.org/10.1136/jmg-2022-109059

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    Data availability statement

    Data are available upon reasonable request. All data that support the findings of this study are available on request from the corresponding authors.

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    Footnotes

    • Twitter @ersoykonas@gmail.com

    • Contributors The study was designed by JA and CTG. Patient recruitment and clinical evaluations were performed by RHK, EG, AP, GT, EK and JA. Human genetic analyses were performed by VA, AT, ND, JA and CTG. Zebrafish studies were performed by VA, ND and CTG. Mouse studies were performed by VA, YK, MH, HK, KH and CTG. The manuscript was drafted by VA, AT, JA and CTG. All authors commented on and approved the final version of the manuscript. CTG is the guarantor.

    • Funding This work was supported by the Agence Nationale de la Recherche Investissements d’Avenir program (ANR-10-IAHU-01), MSDAvenir (Devo-Decode project) and AXA (Tête et Cœur project). VA was supported by the Fondation pour la Recherche Médicale (FDT202106013068) and EUR G.E.N.E. (reference #ANR 17 EURE 0013, part of the Université Paris Cité IdEx #ANR 18 IDEX 0001).

    • 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.