Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

• Published in: Blood advances 2016-11, Vol.1 (1), p.36-46
• Main Authors: Touzot, Fabien, Kermasson, Laetitia, Jullien, Laurent, Moshous, Despina, Ménard, Christelle, Ikincioğullari, Aydan, Doğu, Figen, Sari, Sinan, Giacobbi-Milet, Vannina, Etzioni, Amos, Soulier, Jean, Londono-Vallejo, Arturo, Fischer, Alain, Callebaut, Isabelle, de Villartay, Jean-Pierre, Leblanc, Thierry, Kannengiesser, Caroline, Revy, Patrick
• Format: Article
• Language: English
• Subjects: Genetics; Hematopoiesis and Stem Cells; Human genetics; Human health and pathology; Life Sciences
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2016001313

Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency. •Biallelic RTEL1 mutations generate a large clinical spectrum ranging from classical Hoyeraal-Hreidarsson syndrome to isolated aplastic anemia.