A Proposed Clinical Diagnostic Framework for Short Telomere Syndrome

Area of Science:

• Genetics
• Molecular Biology
• Gerontology

Background:

• Pathogenic genetic variants affecting telomere maintenance genes accelerate telomere length (TL) shortening.
• Shortened TL can be inherited, increasing disease risk in organs like bone marrow, lungs, and liver.
• Diagnosing short telomere-related diseases is complex due to genotype-independent TL inheritance, evolving organ-specific manifestations, and lack of reliable TL cutoffs.

Purpose of the Study:

• Propose 'short telomere syndrome' (STS) as the preferred term over 'telomere biology disorder' (TBD).
• Introduce a phenotype-based approach for classifying STS to guide clinical evaluation and risk stratification.
• Identify research priorities for refining diagnostic thresholds and aligning TL interpretation with disease biology.

Main Methods:

• Review of genetic variants impacting telomere maintenance.
• Analysis of telomere length (TL) inheritance patterns.
• Development of a classification system based on TL percentiles and phenotypic manifestations.

Main Results:

• Proposed STS as a more appropriate term for diseases linked to short telomeres.
• Defined four distinct groups for STS classification: STS, short telomeres with one manifestation, short telomeres without manifestations, and multiple manifestations without short telomeres.
• Highlighted the need for improved diagnostic criteria and risk stratification for short telomere-related conditions.

Conclusions:

• A phenotype-based approach to short telomere syndrome (STS) can improve clinical evaluation and risk stratification.
• Refining diagnostic thresholds and aligning TL interpretation with disease biology are crucial research priorities.
• The proposed classification aims to standardize the diagnosis and management of individuals with short telomeres and related health risks.