Telomere biology disorders

Abstract

Telomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.

Fig. 1. Timeline of significant discoveries and developments in telomere biology and their clinical relevance.

Since dyskeratosis congenita was first described in the early 1900s, there have been significant developments in the knowledge of telomere biology over the last century. It is now known that telomeres are DNA-protein structures found at the ends of chromosomes and provide stability to chromosomes and prevent deterioration during cellular replication. Telomere length attrition thus leads to cellular senescence and triggers cell death pathways. Telomere biology disorders are a group of monogenic disorders of premature aging arising due to accelerated shortening of telomere lengths. It has a highly variable presentation due to various germline mutations and incomplete penetrance. Clinical phenotypes vary from multisystem disorders presenting in childhood such as dyskeratosis congenita and single organ disorders such as idiopathic pulmonary fibrosis, which may present in late adulthood. Despite the significant advancement, the true extent of the syndrome remains unknown and further genetic mutations have yet to be identified.

Fig. 2. Telomere and telomerase complex components and their associated diseases.

Telomeres are noncoding tandem repeats of the sequence TTAGGG, found at the ends of chromosomes in a duplex “D-loop-T-loop” configuration. RTEL1 is a helicase that disrupts T-loops for telomere replication and repair. Shelterin protects telomeres from DNA damage surveillance and comprises of six polypeptide components: TRF1, TRF2, RAP1, TIN2, TPP1 and POT1. Telomerase comprises of the essential components TERT and TERC, which synthesise telomeres and maintain telomere length. Dyskerin forms a complex with NHP2, NOP10 and GAR1. It binds to TERC to stabilise the telomerase complex. TCAB1 regulates the recruitment of telomerase to telomeres. Mutations in any of these components results telomere dysfunction, manifesting as telomere biology disorders. DC, dyskeratosis congenita; GAR1, H/ACA ribonucleoprotein complex subunit 1; HHS, Hoyeraal–Hreidarsson Syndrome; IPF, idiopathic pulmonary fibrosis; NHP2, H/ACA ribonucleoprotein complex subunit 2; NOP10, H/ACA ribonucleoprotein complex subunit 3; POT1, protection of telomeres 1; RAP1, repressor/activator protein 1; RTEL1, regulator of telomere length 1; TCAB1, Telomerase Cajal body protein 1; TERT, telomerase reverse transcriptase; TERC, telomerase RNA component; TIN2, TRF1-interacting nuclear protein 2; TPP1, TIN2-interacting protein 1; TRF1, telomere repeat-binding factor 1; TRF2, telomere repeat-binding factor 2.

Fig. 3. Factors influencing telomere length and attrition.

Schema showing how intrinsic factors such as genetic variants influence telomere length and the influence of exposures and intrinsic factors like age, on telomere attrition.

Fig. 4. The natural history of telomere biology disorders.

Each disorder has its own spectrum of clinical features. Hoyeraal–Hreidarsson Syndrome and Revesz Syndrome present early in childhood and are considered more severe subtypes of dyskeratosis congenita. Dyskeratosis congenita presents commonly in childhood but may manifest at any age. Patients classically present with the mucocutaneous triad of abnormal skin pigmentation, nail dyskeratosis and leukoplakia, and bone marrow failure is the most common cause of death. Idiopathic pulmonary fibrosis is the most common presentation and typically presents after the age of 60. A constellation of premature greying, bone marrow failure, pulmonary fibrosis and cryptogenic liver cirrhosis is suggestive of telomere biology disorders, but due to incomplete penetrance and various inheritance patterns of germline mutations, not all features may be present. The disease demonstrates anticipation with earlier and more severe manifestations down the generations. Across all phenotypes and ages, patients are at an increased risk of cancers.

Fig. 5. Phenotypes of telomere biology disorders.

The heterogenous presentation of telomere biology disorders manifestations may overlap and manifest at various time points or only following certain exposures or insults (e.g., radiation and immunosuppression as preconditioning regimens prior to bone marrow transplant may lead to pulmonary fibrosis in individuals who may have presented with isolated bone marrow failure). Regardless of clinical phenotype, patients are at increased risk of malignancies and disorders of premature aging. DC, dyskeratosis congenita; HHS, Hoyeraal–Hreidarsson Syndrome; ILD, interstitial lung disease; RS, Revesz Syndrome; TBD, telomere biology disorders.

Fig. 6. Proposed pathway for evaluation of suspected telomere biology disorders.

HRCT, high-resolution computed tomography scan; IPF, idiopathic pulmonary fibrosis; PBMC, peripheral blood mononuclear cell; US, ultrasound.