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Expanding the phenotypic spectrum and clinical severity associated with WLS gene

Journal of Human Genetics volume 68, pages 607–613 (2023)Cite this article

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Abstract

WLS (Wnt ligand secretion mediator or Wntless) orchestrates the secretion of all Wnt proteins, a family of evolutionary conserved proteins, involved in Wnt signaling pathway that has many essential biological functions including the regulation of development, cell proliferation, migration and apoptosis. Biallelic variants in WLS have recently been described in 10 patients with pleiotropic multiple congenital anomalies (MCA) known as Zaki syndrome. We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly. These features were reminiscent of Zaki syndrome although variable clinical severity was observed. In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation. As such, we extend the phenotype linked to Zaki syndrome. This study further highlights the importance of a thorough clinical evaluation to delineate the phenotypic spectrum associated with WLS variants and suggests that genotype-phenotype correlations due to variant localization seems likely. However, future work on additional patients and more functional studies may give further insights into genotype-phenotype correlations and the complex function of WLS.

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Data availability

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

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Acknowledgements

We are indebted to the family who participated in this study. HJB was supported by grants from PRO RETINA Deutschland, Stiftung Auge (Deutsche Ophthalmologische Gesellschaft; HJB), Dr. Senckenbergische Stiftung and Köln Fortune (University Hospital of Cologne).

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Author notes

  1. Hanno J. Bolz

    Present address: Senckenberg Centre for Human Genetics, Dr. Senckenbergische Stiftung, 60314, Frankfurt am Main, Germany

Authors and Affiliations

  1. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt

    Ghada M. H. Abdel-Salam, Hanan H. Afifi, Mohamed B. Taher & Ghada El-Kamah

  2. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt

    Mohamed S. Abdel-Hamid

  3. Orodental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt

    Nermeen E. B. Ahmed

  4. Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany

    Holger Thiele & Peter N. Nürnberg

  5. Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany

    Hanno J. Bolz

Authors
  1. Ghada M. H. Abdel-Salam
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Contributions

GA-S, HA, and HB designed and supervised the study. GA-S, HA, GEl-K, MT were actively involved in clinical evaluation and follow-up of the patient and interpreted the brain MRI. MA-H involved in Sanger sequencing. NA performed the oro-dental examination. HB, HT, PN conducted next-generation sequencing and data analysis and interpretation. The first draft of the paper was written by GA-S. All authors had critically reviewed the paper and approved the final version.

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Correspondence to Ghada M. H. Abdel-Salam.

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Abdel-Salam, G.M.H., Afifi, H.H., Abdel-Hamid, M.S. et al. Expanding the phenotypic spectrum and clinical severity associated with WLS gene. J Hum Genet 68, 607–613 (2023). https://doi.org/10.1038/s10038-023-01152-2

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