The genetics and clinical manifestations of telomere biology disorders

Abstract

Telomere biology disorders are a complex set of illnesses defined by the presence of very short telomeres. Individuals with classic dyskeratosis congenita have the most severe phenotype, characterized by the triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. More significantly, these individuals are at very high risk of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in one of six different telomere biology genes can be identified in 50–60% of these individuals. DKC1, TERC, TERT, NOP10, and NHP2 encode components of telomerase or a telomerase-associated factor and TINF2, a telomeric protein. Progressively shorter telomeres are inherited from generation to generation in autosomal dominant dyskeratosis congenita, resulting in disease anticipation. Up to 10% of individuals with apparently acquired aplastic anemia or idiopathic pulmonary fibrosis also have short telomeres and mutations in TERC or TERT. Similar findings have been seen in individuals with liver fibrosis or acute myelogenous leukemia. This report reviews basic aspects of telomere biology and telomere length measurement, and the clinical and genetic features of those disorders that constitute our current understanding of the spectrum of illness caused by defects in telomere biology. We also suggest a grouping schema for the telomere disorders.

Figure 1. Schematic of genes mutated in telomere biology disorders

The chromosome end consists of a (TTAGGG)_n repeats that fold back to form a t-loop. This structure is capped by a six protein complex termed “shelterin.” The telomerase enzyme complex consists of TERT, TERC, DKC1, NOP10, NHP2, and GAR1 (not shown). The inheritance pattern of mutations in these genes is noted. Approximately 50–60% of patients with classic dyskeratosis congenita will have a mutation in one of these genes. Abbreviations: TINF2, TRF1-interacting nuclear factor 2; TERT, telomerase; TERC, telomerase RNA component DKC1, dyskerin; NOP10, NOLA3, nucleolar protein family A, member 3; NHP2, NOLA2, nucleolar protein family A, member 2

Figure 2

Example of lymphocyte telomere length measured by flow cytometry with fluorescence in situ hybridization. Black circle, patient with classic dyskeratosis congenita; blue circle, patient with aplastic anemia; red circle, patient with isolated pulmonary fibrosis. Abbreviations: kb, kilobases; %ile, percentile. Graph courtesy of Drs. Blanche Alter and Peter Lansdorp

Figure 3. The diagnostic triad of dyskeratosis congenita

A. Fingernail dysplasia, B. Toenail dysplasia, C. Leukoplakia of the buccal mucosa, D. Leukoplakia of the tongue, E, and F. Skin pigmentation abnormalities can be diverse and occur anywhere on the body. E. Hyperpigmentation of the neck, F. Hypopigmented areas on the upper thigh.

Figure 4. Example of a family with genetic anticipation due to a TINF2 mutation

The arrow indicates the proband. Mutation carriers and the obligate mutation carrier are shaded black. The history of the proband’s paternal family is not available. Possible, but untested, affected relatives are shown in gray. The history of the proband’s maternal great-grandparents is unknown, but one of them was likely a mutation carrier. Specific medical complications, if present, are noted on the pedigree. The numbers indicate the age in years of the finding. The family is part of our IRB-approved study (132). Lymphocyte telomere lengths measured by flow-FISH are shown. The median lymphocyte telomere length for a healthy 70 year-old is 5.8 kb and for a healthy 24 year-old is 7.6 kb. Abbreviations: SAA, severe aplastic anemia; HSCT, hematopoeitic stem cell transplantation; %ile, percentile for age.

Figure 5. Telomere biology disorders overlap phenotypically and genetically

Patients with DC are the most severely affected and have extremely short telomeres. Telomeres are shorter than normal, although not as short as in DC, in some individuals with aplastic anemia, pulmonary fibrosis, leukemia, fibrotic liver disorders, and possibly others. Genes that are mutated in these disorders are shown in the gray boxes.