Whole exome sequencing in familial isolated primary hyperparathyroidism

  • F. CetaniEmail author
  • E. Pardi
  • P. Aretini
  • F. Saponaro
  • S. Borsari
  • L. Mazoni
  • M. Apicella
  • P. Civita
  • M. La Ferla
  • M. A. Caligo
  • F. Lessi
  • C. M. Mazzanti
  • L. Torregossa
  • A. Oppo
  • C. Marcocci
Original Article



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.


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.


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.


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.


Primary hyperparathyroidism CDC73 GCM2 PARK2 APC Familial adenomatous polyposis 



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

Author 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.


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

Compliance with ethical standards

Conflict of interest

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

Ethical approval

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.

Informed consent

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

Supplementary material

40618_2019_1107_MOESM1_ESM.xlsx (35 kb)
Supplementary material 1 (XLSX 34 kb)


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Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  • F. Cetani
    • 1
    Email author
  • E. Pardi
    • 2
  • P. Aretini
    • 3
  • F. Saponaro
    • 2
  • S. Borsari
    • 2
  • L. Mazoni
    • 2
  • M. Apicella
    • 2
  • P. Civita
    • 3
  • M. La Ferla
    • 3
  • M. A. Caligo
    • 4
  • F. Lessi
    • 3
  • C. M. Mazzanti
    • 3
  • L. Torregossa
    • 5
  • A. Oppo
    • 6
  • C. Marcocci
    • 2
  1. 1.University Hospital of Pisa, Endocrine Unit 2PisaItaly
  2. 2.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  3. 3.Fondazione Pisana per la Scienza ONLUSPisaItaly
  4. 4.Molecular Genetics Unit, Department of Laboratory MedicineUniversity Hospital of PisaPisaItaly
  5. 5.Division of Surgical PathologyUniversity Hospital of PisaPisaItaly
  6. 6.Endocrinology Unit, Department of Medical Sciences and Public HealthUniversity of CagliariCagliariItaly

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