UCSF

Key PointsMutations in telomerase and telomere gene components manifest as diverse clinical syndromes that vary in severity but share a single common molecular defect of shortened telomeres.Telomere length determines disease severity and type in the monogenic telomere syndromes. This is most evidently seen in the pattern of genetic anticipation in families with autosomal-dominant inheritance because mutant telomerase genes cause haploinsufficiency and progressive telomere shortening across generations.Telomere length is a heritable genetic trait even when the telomerase genes are wild-type. Because it is polymorphic, it may influence disease risk across populations.Short telomere length limits the replicative potential of stem cells in high-turnover tissues, such as the bone marrow. This is seen clinically in a failure of haematopoiesis known as aplastic anaemia, which is a common complication of telomere syndromes.Even in tissues of slow turnover, short telomere length causes degenerative disease, as seen in the high prevalence of pulmonary disease in telomerase mutation carriers. In these tissues, short telomere length lowers the threshold to acquired injuries, such as cigarette smoke in the lung.