In summary, we have identified biallelic RTEL1 mutations responsible for a subgroup of HHS, a severe variant of DC. We have also demonstrated that defective human RTEL1 has a detrimental effect on telomere maintenance, suggesting that incorrect resolution of T-loops is a mechanism for telomere shortening in humans. Although previous studies have suggested that RTEL1 is an essential helicase for both telomere maintenance and the regulation of homologous recombination, our study shows that cells harboring biallelic RTEL1 mutations only have significant defects in telomere maintenance. The identification of mutations in RTEL1 extends the sphere of diseases that can be classified as “telomereopathies” and adds to the number of diseases that are caused by defective helicases.