# TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders

## TL;DR

A genetic variant in the TERT gene is common in Ashkenazi Jews and linked to telomere-related diseases, highlighting the need for genetic screening.

## Contribution

Identifies TERT p.K1050N as a founder variant in Ashkenazi Jews associated with telomere biology disorders.

## Key findings

- The TERT p.K1050N variant shows a shared haplotype block, supporting a founder effect in Ashkenazi Jewish populations.
- p.K1050N reduces telomerase activity and impairs cell proliferation, contributing to telomere biology disorders.
- Clinical assessments confirm p.K1050N's role in TBD phenotypes and shortened telomeres with incomplete penetrance.

## Abstract

Pathogenic germline variants in telomerase (TERT) cause telomere biology disorders (TBDs) and are associated with bone marrow failure, pulmonary fibrosis, and other complications. TERT c.3150 G > C (p.K1050N) is frequent in the Ashkenazi Jewish (ASH) population and has been identified in ASH families with TBDs. Whole-genome sequencing of 96 p.K1050N heterozygotes from the UK Biobank and All of Us databases revealed a shared haplotype block, supporting a founder effect. Analyses of 15 additional p.K1050N cases validated this haplotype and identified mitochondrial and Y-STR haplogroups consistent with ASH ancestry. Clinical assessments showed that p.K1050N contributes to TBD phenotypes and shortened telomeres, while population data suggest incomplete penetrance. p.K1050N reduces telomerase activity and processivity, and decreases PCNA expression and BrdU incorporation, impairing cell proliferation. Our findings establish TERT p.K1050N as an ASH founder variant associated with TBDs, underscoring the need for genetic screening and long-term clinical studies.