**Acknowledgements**

decades in the onset of the disease between generations with IPF manifesting in older indi‐

The heterogeneous presentation of telomere biology diseases make difficult their diagnosis as already mentioned in the description of DC (section 2.3.1]. In addition, some of the symptoms also occur in patients with other diseases. For example, inherited bone marrow failure is also observed in patients with Fanconi anemia, Shwachmann-Diammond syndrome and other inherited BMFs. However, differentiating DC-associated BMF is important for patient management since, for example, these patients often do not respond to immunosuppressive therapy. One important criterion for diagnosis of telomere biology disorders is the presence of short telomeres in comparison to the aged healthy population, usually lower than the 1% percentile. However, some IPF patients present short telomeres even in the absence of mutations in telomere biology related genes [167]. Therefore, an accurate diagnosis requires establishing the molecular basis of the disease, identifying the causative mutation. Molecular diagnosis can be done sequencing the exons contained in the genes presently known to be mutated in telomere biology disorders. However, the high number of candidate genes and the large number of exons present in some of them makes this approach time-consuming and expensive. Alternatively, sequencing by exome sequencing techniques all exons of patients and close relatives is becoming a more attractive, faster and cheaper method [84]. In addition, exome sequencing allows the identification of mutations in genes that have not been previously

These diseases can be considered and example of the importance of precision medicine for diagnosis but also for patient managing and genetic counselling. The importance in diagnosis is enforced by the elevated heterogeneity of the clinical presentations in several systems that can create some uncertainty until a genetic analysis is performed. The importance for patient management derives from the possible progressive alteration of different organs, as mentioned above. This progression with time is very characteristic of telomerase biology disorders and can only be predicted by a precise molecular diagnosis. Disease progression also determines the therapeutic treatment. As mentioned above, the only curative alternatives are organ transplantation, either hematopoietic stem cell transplantation (HSCT) or lung transplanta‐ tion. However, in telomere biology disorders both transplants have specific complications. Reduced intensity conditioning is advised and patients frequently present graft failure. In the case of HSCT respiratory complications have been described. In contrast, haematological, renal and infectious complications were observed after lung transplantation. Both complications

Precision medicine is also important for genetic counselling in telomere biology disorders [12]. Depending on the mutation, these diseases can have different manners of inheritance. The phenotypic penetrance of each mutation can be different. Heterozygous clinically silent carriers can be found whose long-term evolution is not yet understood. Patients treated for a symptom can develop a different one later on. As mentioned above, supportive measures and close follow-up of patients and carrier relatives is also very important. All these characteristics, specific to these diseases, might be difficult to transmit to the patients and their relatives what

viduals (mean 51 years) and bone marrow failure in younger ones [14 years) [172].

100 Telomere - A Complex End of a Chromosome

related to telomere biology (see [128] for a recent example).

could be expected for the multi-systemic nature of these diseases.

This work was supported by grant PI1401495 from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain, supported by FEDER funds. CM-G is supported by the CIBER de Enfermedades Raras (CIBERER).
