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Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene

Journal of Human Genetics volume 68, pages 273–279 (2023)Cite this article

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Abstract

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

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Acknowledgements

We thank Francesco Saettini for his effort to re-assess the parents of a patient with FNIP1 deficiency for skin lesions.

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Authors and Affiliations

  1. Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Irma van de Beek, Johan J. P. Gille, Abeltje M. Polstra, Alex V. Postma, Arjan C. Houweling & Quinten Waisfisz

  2. Department of Human Genetics, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Iris E. Glykofridis, Jesper A. Balk & Rob M. F. Wolthuis

  3. Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Michael W. T. Tanck

  4. Department of Dermatology and GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands

    Monique N. H. Luijten

  5. Department of Dermatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands

    Theo M. Starink

  6. Department of Surgery, Gelderse Vallei Ziekenhuis, Ede, The Netherlands

    Paul C. Johannesma

  7. Division of Biomedical Genetics, Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Eric Hennekam

  8. Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Maurice J. B. van den Hoff, Quinn D. Gunst & Alex V. Postma

  9. Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

    Pieter E. Postmus

  10. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Maurice A. M. van Steensel

  11. Singapore Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore

    Maurice A. M. van Steensel

  12. Family Cancer Clinic, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Fred H. Menko

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  1. Irma van de Beek
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Contributions

All authors have contributed sufficiently to the intellectual content of the submission. Conceived and/or designed the work that led to the submission, acquired data, and/or played an important role in interpreting the results: IvdB, IEG, MWTT, MNHL, TMS, JAB, PCJ, EH, MJBH, QDG, JJPG, AMP, PEP, MAMS, AVP, RMFW, FHM, ACH, and QW. Drafted or revised the manuscript: IvdB, IEG, MNHL, RMFW, ACH, and QW. Approved the final version: IvdB, IEG, MWTT, MNHL, TMS, JAB, PCJ, EH, MJBH, QDG, JJPG, AMP, PEP, MAMS, AVP, RMFW, FHM, ACH, and QW.

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Correspondence to Irma van de Beek.

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van de Beek, I., Glykofridis, I.E., Tanck, M.W.T. et al. Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene. J Hum Genet 68, 273–279 (2023). https://doi.org/10.1038/s10038-022-01113-1

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