Subclinical Telomere Biology Disorder in Cancer Patients Heterozygous for the RTEL1 R1264H Founder Variant

RTEL1 R1264H is a founder variant with a carrier frequency of 0.3%-1.0% in the Ashkenazi Jewish population. While biallelic RTEL1 R1264H causes a severe form of telomere biology disorder (TBD) presenting in childhood, the clinical significance of monoallelic carrier status has remained uncertain, limiting effective counseling and management. Here, we describe the clinical features, telomere lengths, and tumor somatic profiles of cancer patients found to be heterozygous for RTEL1 R1264H to evaluate for evidence of subclinical TBD in this population. Among 39,337 individuals who underwent RTEL1 germline analysis via MSK-IMPACT, 32 (0.08%) were incidentally found to be heterozygous for RTEL1 R1264H. Three individuals (9%) met diagnostic criteria for TBD based on compatible clinical features and telomere shortening, and two additional individuals (6%) had histories suspicious for TBD but did not have telomere length data available. Notably, 7 individuals (22%) experienced severe or fatal therapy-related toxicities, despite many lacking other clinical features of a TBD. These findings support that RTEL1 R1264H can act in an autosomal dominant fashion and confer TBD disease risk, albeit with low penetrance, and may increase susceptibility to treatment-related complications.