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

Author(s):Show less -

Gutierrez-Rodrigues, Fernanda ^[1] ; Masri, Nohad ^[2] ; Chouery, Eliane ^[3] ; Diamond, Carrie ^[1] ; Jalkh, Nadine ^[3] ; Vicente, Alana ^[1] ; Kajigaya, Sachiko ^[1] ; Abillama, Fayez ^[2] ; Bejjani, Noha ^[2] ; Serhal, Wassim ^[2] ; Calado, Rodrigo T. ^[4] ; Young, Neal S. ^[1] ; Farhat, Hussein ^[2] ; Coussa, Marie Louise ^[2]

Affiliation

^[1] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 - USA

^[2] LAUMC RH, LAU Gilbert & Rose Marie Chagoury Sch Med, Zahar St, Beirut 1110 - Lebanon

^[3] St Joseph Univ, Fac Med, Unite Genet Med, Beirut - Lebanon

^[4] Univ Sao Paulo, Dept Med Imaging Hematol & Clin Oncol, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Human Genetics; v. 138, n. 11-12, p. 1323-1330, DEC 2019.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC