Telomeres are supramolecular structures that allow the DNA strand to fold back on itself and protect the linear chromosome end from being sensed as a double-strand DNA break. Telomeric conservation relies on mechanisms that replace terminal DNA sequences, and ensuring structural integrity. Telomere biology disorders (TBDs) are a heterogeneous group of low-prevalence pathologies defined by germline mutations in genes involved in telomere maintenance mechanisms (TMMs). TBDs manifest across a broad clinical spectrum, often with substantial phenotypic and genetic overlap among clinical entities. In this issue of
EMBO Molecular Medicine
, Tummala and collaborators present clinical and biological data from DC/DCL patients, that enhances the understanding of the natural history of these diseases. In addition, the description of novel TBD-associated genetic variants in
POT1
and
ZCCHC8
and of the new
POLA1
gene advances the understanding of the functional network of genes involved in TBD and highlights new pathogenic mechanisms.