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Blood Adv. 2016 Nov 22;1(1):36-46. doi: 10.1182/bloodadvances.2016001313. eCollection 2016 Nov 29.

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations.

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Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Service d'Immunologie, d'Hématologie et Rhumatologie Pédiatriques, Paris, France.
Centre d'investigation clinique-Biothérapie 502 INSERM, Paris, France.
Département de Biothérapie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
INSERM Unité Mixte de Recherche (UMR) 1163, Laboratory of Genome Dynamics in the Immune System, Paris, France.
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
AP-HP Service de Génétique, Hôpital Bichat, Paris, France.
Department of Pediatric Immunology and Allergy, Ankara University Medical School, Dikimevi, Ankara, Turkey.
Department of Pediatric Gastroenterology, Gazi University Medical School, Beştepe, Ankara, Turkey.
Département de pédiatrie, Centre Hospitalier du Mans, Le Mans, France.
Division of Pediatrics and Immunology, Faculty of Medicine, Ruth Rappaport Children Hospital, Technion, Haifa, Israel.
Institute of Hematology, INSERM UMR944/Centre national de la recherche scientifique (CNRS) UMR7212, Saint-Louis Hospital, Paris, France.
University Paris Diderot, Sorbonne Paris Cité, Paris, France.
Institut Curie, Paris Sciences et Lettres Research University, CNRS, UMR 3244, Telomeres and Cancer Laboratory, Paris, France.
Sorbonne Universités, Université Pierre et Marie Curie University Paris 06, CNRS, UMR3244, Paris, France.
Immunology and Pediatric Hematology Department, AP-HP, Paris, France.
Inserm UMR 1163, Paris, France.
Collège de France, Paris, France.
CNRS UMR7590, Sorbonne Universités, Université Pierre et Marie Curie Paris 6-Muséum national d'histoire naturelle-Institut de recherche pour le développement-Institut universitaire de cancérologie, Paris, France.
Service d'hématologie pédiatrique, Hôpital Robert-Debré, Paris, France; and.
Centre de référence des aplasies médullaires, Sorbonne Paris Cité, Paris, France.


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.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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