Pathogenic TERT promoter variants in telomere diseases

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• TERT promoter (TERTp) variants are implicated in tumorigenesis.
• Previously, TERTp variants in nonmalignant diseases were primarily observed in idiopathic pulmonary fibrosis (IPF) linked to germline telomere gene defects.

Purpose of the Study:

• To investigate the presence and significance of TERT promoter variants in a wider range of telomeropathies.
• To determine the association of TERT promoter variants with clinical phenotypes and genetic backgrounds in affected individuals and their families.

Main Methods:

• Screening of 136 patients with telomeropathies, 52 relatives, and 195 controls for TERT promoter variants using a custom massively parallel sequencing assay.
• Analysis of variant presence, co-occurrence with germline telomere gene variants, and correlation with clinical parameters such as blood counts, telomere length, and treatment response.

Main Results:

• Pathogenic TERT promoter variants (-124, -146) were found in 7% of unrelated patients with IPF, aplastic anemia, and cirrhosis.
• Relatives carrying these variants also had pathogenic germline telomere gene variants.
• TERTp variant acquisition was specific to patients with telomeropathies, often co-occurred with TERT germline variants, and was associated with aging, but not peripheral blood counts or telomere length.

Conclusions:

• Pathogenic TERT promoter variants are associated with a broader spectrum of nonmalignant conditions, including marrow failure and liver disease, stemming from inherited telomerase deficiency.
• Identifying TERT promoter variants can aid in assessing the pathogenicity of uncertain constitutional variants in telomere-related diseases.