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New Insight into the genotype-phenotype correlation of PTH1R variants and primary failure of tooth eruption on an Italian Cohort

European Journal of Human Genetics volume 32, pages 1402–1411 (2024)Cite this article

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Abstract

Primary failure of tooth eruption (PFE) is an autosomal dominant disease with penetrance defect. While the clinical phenotype is relatively well-defined since the 70 s of the last centuries, much more need to be clarified about the genetic causes of this condition. In our previous paper we established clinical criteria to better identify PFE patients carrying PTH1R gene variants. We examined a new cohort of 32 patients, including one or more relatives for 7 patients (43 cases in total), referred to have PFE and recruited from our Hospital and from external outpatients. Sequencing analysis of the PTH1R coding sequence in this cohort of patients revealed 9 different variants, 4 exonic and 5 intronic. Through in silico prediction tools and databases, 3 of them (2 exonic and 1 in a splicing site) had been considered potentially involved in the PFE phenotype. Sequencing of cDNA was unsuccessfully attempted due to the low levels of PTH1R expression in the analysed tissues. The yield of the genetic test increases when the clinical selection of the patients with dental eruption failure is well-characterized. Dental eruption failure with pure clinical findings of PFE associated with familial history revealed variants in PTH1R gene, offering a diagnostic test for the family. Characterization of novel variants in the most relevant responsible gene of the PFE could bring to a more accurate diagnosis and therapeutic approach in the future and to a deeper comprehension of the disease.

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Fig. 1: Molecular description of c.720 G > C;p.(Lys240Asn) (K240N) variant and main clinical findings of patients #59.
Fig. 2: Molecular description of c.580 G > C;p.(Gly194Arg) (G194R) variant and main clinical findings of patients #68.
Fig. 3: Root Mean Square Deviation (RMSD) of the PTH1R transmembrane domains (TM).

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Data supporting the conclusions of this article are all included within the article.

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Acknowledgements

We gratefully acknowledge patients and their families for their consent and valuable support of our work.

Funding

This study was funded from Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS “Ricerca Corrente 2023” (to PC and ET).

Author information

Author notes

  1. These authors contributed equally: Clarissa Modafferi, Elisabetta Tabolacci.

Authors and Affiliations

  1. UOC Genetica Medica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy

    Clarissa Modafferi, Filomena Lo Vecchio, Ilaria Cassano, Roberto Bertozzi, Arcangelo Fargnoli & Pietro Chiurazzi

  2. Dipartimento di Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy

    Elisabetta Tabolacci & Pietro Chiurazzi

  3. Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy

    Elisabetta Tabolacci, Alessandro Arcovito & Pietro Chiurazzi

  4. Medical Oncology, SG Moscati Hospital, Statte, Ta, Italy

    Concetta Cafiero

  5. Anatomic Pathology Unit, Fabrizio Spaziani Hospital, Frosinone, Italy

    Concetta Cafiero

  6. Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Sezione di Biochimica, Università Cattolica del Sacro Cuore, Rome, Italy

    Ettore Lo Cascio & Alessandro Arcovito

  7. UOC di Clinica Odontoiatrica, Dipartimento di Neuroscienze, Organi di senso e Torace, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy

    Cristina Grippaudo

  8. Dipartimento Universitario Testa Collo ed Organi di Senso, Università Cattolica del Sacro Cuore, Rome, Italy

    Cristina Grippaudo

Authors
  1. Clarissa Modafferi
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  2. Elisabetta Tabolacci
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  3. Filomena Lo Vecchio
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  4. Ilaria Cassano
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  5. Roberto Bertozzi
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  6. Arcangelo Fargnoli
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  7. Concetta Cafiero
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  8. Ettore Lo Cascio
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  9. Alessandro Arcovito
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  10. Cristina Grippaudo
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  11. Pietro Chiurazzi
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Contributions

Conceptualization, CM, ET, CG, and PC; methodology, CM, ET, FLV, IC, RB. AF and ELC; formal analysis, CM, ET, AA, CG, PC; investigation, CM, ET, FLV, IC, RB. AF and ELC; data curation, CM, ET, AA, CG, PC; writing - original draft preparation, CM, ET, CG, and PC writing - review and editing, CM, ET, AA, CG, and PC. All authors have read and agreed to the submitted version of the manuscript.

Corresponding author

Correspondence to Cristina Grippaudo.

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Competing interests

The authors declare no competing interests.

Ethical approval

The study protocol was approved by the Ethic Committee of the Catholic University of Sacred Heart of Rome (ID 565-11/2015). Written informed consent was obtained from all patients/legal tutors/parents. The work adhered to the principles outlined in the Declaration of Helsinki.

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Modafferi, C., Tabolacci, E., Lo Vecchio, F. et al. New Insight into the genotype-phenotype correlation of PTH1R variants and primary failure of tooth eruption on an Italian Cohort. Eur J Hum Genet 32, 1402–1411 (2024). https://doi.org/10.1038/s41431-024-01691-y

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