A Proposed Clinical Diagnostic Framework for Short Telomere Syndrome

Pathogenic genetic variants in telomere maintenance genes can lead to accelerated telomere length (TL) shortening. Individuals can pass on significantly shortened TL to their offspring, with or without transmission of the causal genetic variant. Carriers and their progeny are at increased risk for disease in organ systems with high life-time replicative demand, including bone marrow, lungs, and liver. The diagnosis of short telomere related disease is complicated by three factors: the potential for TL inheritance independent of genotype; organ-specific manifestations that evolve across the lifespan; and the lack of a TL cutoff that reliably predicts phenotypic disease. In this manuscript, we suggest that short telomere syndrome (STS) rather than telomere biology disorder (TBD) is the appropriate term for these diseases. We propose a phenotype-based approach to STS that distinguishes among four groups: (1) STS (TL < 10th age adjusted percentile in PBMCs with multiple phenotypic manifestations); (2) short telomeres with one phenotypic manifestation; (3) short telomeres without phenotypic manifestations; and (4) multiple phenotypic manifestations without short telomeres. This approach is intended to guide clinical evaluation of patients with short telomeres and longitudinal risk stratification. We also identify research priorities needed to refine diagnostic thresholds and align TL interpretation with disease biology.