Beginning at the ends: telomeres and human disease

Abstract

Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.

Keywords: Coats plus; Hoyeraal Hreidsarsson syndrome; cancer; dyskeratosis congenita; epidemiology; telomere; telomere biology disorder.

Figure 1.. Factors associated with human disease are integrally connected to telomere biology.

This schematic illustrates the complex relationships between telomere biology, disease, aging, genetics, and environmental exposures, all of which should be considered in studies of telomeres and human disease.

Figure 2.. Mucocutaneous features of dyskeratosis congenita of an adult male whose disease is due to a DKC1 mutation.

( A) Dystrophic and ridged fingernails. ( B) Hyper- and hypo-pigmented skin of neck and upper chest. ( C) Irregular leukoplakia of the tongue.

Figure 3.. Proteins encoding key components of telomere biology associated with disease.

Protein names are noted in the figure. Associated disease and mode(s) of inheritance are shown in Table 1. The asterisk indicates proteins encoded by genes with single-nucleotide polymorphisms associated with cancer. The pound sign indicates proteins encoded by genes with single-nucleotide polymorphisms associated with telomere length.

Figure 4.. Schematic representation of the connections between age, telomere length, and human disease.

Clinically significant telomeres associated with telomere biology disorders are generally at or below the first percentile for age (blue shape). Many association studies of telomere length and human phenotypes, including cancer, have identified statistically significant, but perhaps not clinically significant, differences in telomere length between cases and controls (represented by yellow and red). Some studies have identified rare families with germline mutations in components of the shelterin telomere protection complex as associated with longer telomeres (green shape). AA, aplastic anemia; CLL, chronic lymphocytic leukemia; CP, Coats plus; DC, dyskeratosis congenita; FM, familial melanoma; HH, Hoyeraal Hreidarsson syndrome; LD, liver disease; LFL, Li-Fraumeni-like syndrome; MDS, myelodysplastic syndrome; PF, pulmonary fibrosis; RS, Revesz syndrome.

Figure 5.. Relationship between telomere length, variant allele frequency, and human disease.

The majority of genetic variants associated with common disease have a minor allele frequency (MAF) greater than 1% and telomeres in the “normal” range (that is, between the 1st and 99th percentiles for age). In contrast, genetic variants associated with rare and more highly penetrant disease are rare with MAF often much less than 1% and the extremes of telomere length. AA, aplastic anemia; CLL, chronic lymphocytic leukemia; CP, Coats plus; DC, dyskeratosis congenita; FM, familial melanoma; HH, Hoyeraal Hreidarsson syndrome; LD, liver disease; LFL, Li-Fraumeni-like syndrome; MDS, myelodysplastic syndrome; PF, pulmonary fibrosis; RS, Revesz syndrome.