A Balanced Chromosomal Rearrangement Disrupting the Telomerase RNA Component Gene Causes Short Telomere-Mediated Pulmonary Fibrosis

Excessive telomere shortening contributes to pulmonary fibrosis (PF), with at least 30% of familial cases attributed to telomere biology disorders (TBDs). However, TBD-associated PF remains underdiagnosed because of unidentified disease-causing mutations and limited referral for telomere and genetic testing. Here, we combined telomeric restriction fragment analysis, telomere analysis by a long-read Nanopore sequencing method (NanoTelSeq), exome sequencing (ES), and optical genome mapping (OGM) to investigate the underlying cause of disease in a family affected by PF, microcephaly, and premature hair graying. We identified a familial balanced translocation associated with short telomeres, which involved a chromosome 3 breakpoint within the non-coding telomerase RNA component (TERC) gene, disrupting the 451-nucleotide telomerase RNA. Establishing the diagnosis enabled a TBD-tailored protocol and successful lung transplantation in the proband at age 49. These findings identified structural disruption of TERC as a previously unrecognized cause of TBD and broadened the genetic landscape of TBD beyond splicing, single nucleotide substitutions, and insertion/deletion variants. Furthermore, they demonstrated the importance of routine telomere length measurement alongside comprehensive genomic testing in familial PF.