Disorders of Telomere Length

AbstractRecent discoveries have uncovered roles for telomere length, at both short and long extremes, as a driver of inherited disease risk in children and adults. For short telomere length the predominant phenotype is degenerative, with immunodeficiency, bone marrow failure, and pulmonary disease being most common. Short telomere syndrome genetics inform clinical decisions and have transformed understanding of the etiology, natural history, and treatment of common diseases such as idiopathic pulmonary fibrosis. At the other extreme, ultra-long telomere length predisposes to neoplasia including lympho- and myeloproliferative disease. Individuals with mutations that lengthen telomeres may show features of youthfulness such as delayed hair graying but paradoxically are at risk for benign and malignant neoplasia, which are associated with aging. Their earliest events are traceable in the blood as premature onset of clonal hematopoiesis which shows complete penetrance with aging. Here, we review the genetic basis, pathophysiology, and contrasting phenotypes of Mendelian short and long telomere syndromes, emphasizing how they inform clinical decisions as well as our understanding of the fundamentals of aging and cancer.