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A novel homozygous RTEL1 variant in a consanguineous Lebanese family: phenotypic heterogeneity and disease anticipation

  • Fernanda Gutierrez-Rodrigues
  • Nohad Masri
  • Eliane Chouery
  • Carrie Diamond
  • Nadine Jalkh
  • Alana Vicente
  • Sachiko Kajigaya
  • Fayez Abillama
  • Noha Bejjani
  • Wassim Serhal
  • Rodrigo T. Calado
  • Neal S. Young
  • Hussein FarhatEmail author
  • Marie Louise Coussa
Original Investigation
  • 59 Downloads

Abstract

Phenotypic heterogeneity is often observed in patients with telomeropathies caused by pathogenic variants in telomere biology genes. However, the roles of recessive variants in these different phenotypes are not fully characterized. Our goal is to describe the biological roles of a novel homozygous RTEL1 variant identified in a consanguineous Lebanese family with unusual presentation of telomeropathies. A proband was screened for germline variants in telomere biology genes by whole exome sequencing. Leukocytes’ telomere length was measured in the proband and eight relatives. We identified a novel homozygous p.E665K RTEL1 variant in the proband, his mother, and seven siblings that associated with telomere shortening and a broad spectrum of clinical manifestations, ranging from mild unspecific findings to severe phenotypes. Consanguinity in at least three family generations led to increased frequency of the homozygous p.E665K variant in the youngest generation and progressive telomere shortening. The increased frequency of the homozygous RTEL1 variant due to consanguinity in this Lebanese family allowed us to infer novel behaviors of recessive RTEL1 variants, as the expressivity and penetrance of this gene are very heterogenous between inter- and intra-generations. Progressive telomere shortening was associated with disease anticipation, first reported in recessive autosomal telomeropathies. Both genetic testing and telomere length measurement were critical for the clinical diagnosis of this family with telomere diseases marked by phenotypic heterogeneity.

Notes

Acknowledgements

This work was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute/NIH, and by grants from Saint Joseph University, Beirut, Lebanon and the São Paulo Research Foundation/CAPES (FAPESP; Grant Number, 13/08135-2). We would like to thank the Bioinformatics and Computational Core Facility at the NHLBI for data analysis.

Author contributions

Contribution: FGR, NM, EC, and HF wrote the article, performed experimental assays and collected clinical data. AV and CD contributed to experimental assays and data analysis; EC and NJ contributed for sequencing bioinformatics data analysis and study design; NM, FA, WS, NB, HF, and MLC contributed to patients’ recruitment and data analysis; RTC contributed to telomere length measurement analysis; NSY, HF, and MLC contributed to study design, data interpretation and both had full access to all the data in this study and had final responsibility for the decision to submit for publication. FGR, NM, EC, CD, SK, RTC, NSY, HF, and MLC critically reviewed the manuscript for intellectual content.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

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Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Fernanda Gutierrez-Rodrigues
    • 1
  • Nohad Masri
    • 2
  • Eliane Chouery
    • 3
  • Carrie Diamond
    • 1
  • Nadine Jalkh
    • 3
  • Alana Vicente
    • 1
  • Sachiko Kajigaya
    • 1
  • Fayez Abillama
    • 2
  • Noha Bejjani
    • 2
  • Wassim Serhal
    • 2
  • Rodrigo T. Calado
    • 4
  • Neal S. Young
    • 1
  • Hussein Farhat
    • 2
    Email author
  • Marie Louise Coussa
    • 2
  1. 1.Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), NIHBethesdaUSA
  2. 2.LAU Gilbert and Rose-Marie Chagoury School of MedicineLAUMC/RHBeirutLebanon
  3. 3.Unité de Génétique Médicale, Faculty of MedicineSaint Joseph UniversityBeirutLebanon
  4. 4.Department of Medical Imaging, Hematology, and Clinical OncologyUniversity of São PauloRibeirão PretoBrazil

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