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Identification of a CDH12 potential candidate genetic variant for an autosomal dominant form of transgrediens and progrediens palmoplantar keratoderma in a Tunisian family

Journal of Human Genetics volume 65, pages 397–410 (2020)Cite this article

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Abstract

Molecular diagnosis of rare inherited palmoplantar keratoderma (PPK) is still challenging. We investigated at the clinical and genetic level a consanguineous Tunisian family presenting an autosomal dominant atypical form of transgrediens and progrediens PPK to better characterize this ultrarare disease and to identify its molecular etiology. Whole-exome sequencing (WES), filtering strategies, and bioinformatics analysis have been achieved. Clinical investigation and follow up over 13 years of this Tunisian family with three siblings formerly diagnosed as an autosomal recessive form of Mal de Melela-like conducted us to reconsider its initial phenotype. Indeed, the three patients presented clinical features that overlap both Mal de Meleda and progressive symmetric erythrokeratoderma (PSEK). The mode of inheritance was also reconsidered, since the mother, initially classified as unaffected, exhibited a similar expression of the disease. WES analysis showed the absence of potentially functional rare variants in known PPKs or PSEK-related genes. Results revealed a novel heterozygous nonsynonymous variant in cadherin-12 gene (CDH12, NM_004061, c.1655C > A, p.Thr552Asn) in all affected family members. This variant is absent in dbSNP and in 50 in-house control exomes. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in cadherin-12 protein destabilization and thermal instability. Functional annotation and biological network construction data provide further supporting evidence for the potential role of CDH12 in the maintenance of skin integrity. Taken together, these results suggest that CDH12 gene is a potential candidate gene for an atypical presentation of an autosomal dominant form of transgrediens and progrediens PPK.

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Acknowledgements

We would like to warmly acknowledge the patients and their families for their collaboration and all clinicians involved the care of the patients.

Funding

This work was supported by the Tunisian Ministry of Public Health, the Ministry of Higher Education and Scientific Research (LR16IPT05), and RARE-MED project (A* MIDEX Initiative d’excellence). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Sahar Elouej

    Present address: Marseille Medical Genetics U 1251, Aix Marseille Université Faculté de Médecine de la Timone, Marseille, France

Authors and Affiliations

  1. Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Pasteur Institute of Tunis, University of Tunis El Manar, Tunis, Tunisia

    Cherine Charfeddine, Hamza Dallali, Ghaith Abdessalem, Yosr Hamdi, Sahar Elouej, Zied Landoulsi & Sonia Abdelhak

  2. High Institute of Biotechnology of Sidi Thabet, Biotechpole of Sidi Thabet, University of Manouba, 2020, Ariana, Tunisia

    Cherine Charfeddine

  3. Laboratory of Bioinformatics, Biomathematics and Biostatistics - LR16IPT09, Pasteur Institute of Tunis, University Tunis El Manar, Tunis, Tunisia

    Kais Ghedira

  4. Bioinformatics Core, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Sur-Alzette, Luxembourg

    Zied Landoulsi

  5. Génétique et Physiologie de l’Audition, Institut Pasteur, INSERM UMRS1120, Sorbonne University, 75015, Paris, France

    Aziz El-Amraoui

  6. Laboratory of Human and Experimental Pathology, Pasteur Institute of Tunis, Tunis, Tunisia

    Mohamed Samir Boubaker

  7. Department of Dermatology, CHU La Rabta Tunis, 1007, Tunis, Tunisia

    Mourad Mokni

  8. Marseille Medical Genetics U 1251, Aix Marseille Université Faculté de Médecine de la Timone, Marseille, France

    Valérie Delague, Arnaud Lagarde & Nicolas Levy

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Charfeddine, C., Dallali, H., Abdessalem, G. et al. Identification of a CDH12 potential candidate genetic variant for an autosomal dominant form of transgrediens and progrediens palmoplantar keratoderma in a Tunisian family. J Hum Genet 65, 397–410 (2020). https://doi.org/10.1038/s10038-019-0711-4

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