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Whole exome sequencing in familial isolated primary hyperparathyroidism

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Abstract

Purpose

Familial isolated hyperparathyroidism (FIHP) is a rare inherited disease accounting for 1% of all cases of primary hyperparathyroidism (PHPT). It is genetically heterogeneous being associated with mutations in different genes, including MEN1, CDC73, CASR, and recently GCM2. The aim of the study was to further investigate the molecular pathogenesis in Italian FIHP kindreds.

Methods

We used whole exome sequencing (WES) in the probands of seven unrelated FIHP kindreds. We carried out a separate family-based exome analysis in a large family characterized by the co-occurrence of PHPT with multiple tumors apparently unrelated to the disease. Selected variants were also screened in 18 additional FIHP kindreds. The clinical, biochemical, and pathological characteristics of the families were also investigated.

Results

Three different variants in GCM2 gene were found in two families, but only one (p.Tyr394Ser), already been shown to be pathogenic in vitro, segregated with the disease. Six probands carried seven heterozygous missense mutations segregating with the disease in the FAT3, PARK2, HDAC4, ITPR2 and TBCE genes. A genetic variant in the APC gene co-segregating with PHPT (p.Val530Ala) was detected in a family whose affected relatives had additional tumors, including colonic polyposis.

Conclusion

We confirm the role of GCM2 germline mutations in the pathogenesis of FIHP, although at a lower rate than in the previous WES study. Further studies are needed to establish the prevalence and the role in the predisposition to FIHP of the novel variants in additional genes.

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Change history

  • 26 September 2019

    Unfortunately, the 13th author name has been published incorrectly in the original publication.

  • 26 September 2019

    Unfortunately, the 13th author name has been published incorrectly in the original publication.

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Acknowledgements

The authors thank the families involved in this study for their participation.

Funding

This work was supported by Progetti di Ricerca di Ateneo (PRA)—2015—of the University of Pisa (C.M.).

Author information

Author notes

  1. F. Cetani and E. Pardi contributed equally to the work.

Authors and Affiliations

  1. University Hospital of Pisa, Endocrine Unit 2, Via Paradisa 2, 56124, Pisa, Italy

    F. Cetani

  2. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    E. Pardi, F. Saponaro, S. Borsari, L. Mazoni, M. Apicella & C. Marcocci

  3. Fondazione Pisana per la Scienza ONLUS, Pisa, Italy

    P. Aretini, P. Civita, M. La Ferla, F. Lessi & C. M. Mazzanti

  4. Molecular Genetics Unit, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy

    M. A. Caligo

  5. Division of Surgical Pathology, University Hospital of Pisa, Pisa, Italy

    L. Torregossa

  6. Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy

    A. Oppo

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  1. F. Cetani
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Contributions

FC and EP contributed equally to this report. Conceptualization and design of the experiments: FC, EP, PA, MAC, and CMM. Patients managing: FC, FS, LM, MA, AO, and CM. Collection and histological examination of tissue samples: LT. Genetic and whole exome sequencing analyses: EP, PA, SB, PC, MLF, FL, and CMM. Analysis of whole exome sequencing data: PA and EP. Contribution to the interpretation of the results: FC, EP, SB, and CMM. Drafting of the manuscript: FC, EP, PA, and SB. Critical revision of the article: FC, EP, PA, FS, SB, CMM, and CM. All authors read and approved the final manuscript.

Corresponding author

Correspondence to F. Cetani.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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The study was reviewed and approved by the University Hospital of Pisa Ethics Committee, and in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Cetani, F., Pardi, E., Aretini, P. et al. Whole exome sequencing in familial isolated primary hyperparathyroidism. J Endocrinol Invest 43, 231–245 (2020). https://doi.org/10.1007/s40618-019-01107-5

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