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Orphanet J Rare Dis. 2018 Aug 17;13(1):139. doi: 10.1186/s13023-018-0864-9.

Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders.

Author information

1
Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, P.O.BOX 281, FI-0029, Helsinki, Finland.
2
Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Building 6M, SE-901 87, Umeå, Sweden.
3
Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, PL 372, 00029 HUS, Helsinki, Finland.
4
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
5
Paris Descartes University, Imagine Institute, 24 boulevard du Montparnasse, 75015, Paris, EU, France.
6
Department of Medical Biosciences, Pathology, Umeå University, NUS, Dept of Medical Biosciences M21, 901 85, Umeå, Sweden.
7
Department of Haematology, Helsinki University Hospital Comprehensive Cancer Center and University of Helsinki, Helsinki, Finland.
8
Faculty of Medicine Department of Virology and Department of Oral and Maxillofacial Surgery, University of Helsinki and Helsinki University Hospital, POB 21, 00014, Helsinki, Finland.
9
Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden.
10
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065, USA.
11
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
12
Howard Hughes Medical Institute, New York, USA.
13
Rare Disease Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
14
Adult Immunodeficiency Unit, Department of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
15
Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, P.O.BOX 281, FI-0029, Helsinki, Finland. Janna.saarela@helsinki.fi.

Abstract

BACKGROUND:

The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.

METHODS:

Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.

RESULTS:

In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.

CONCLUSIONS:

Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

KEYWORDS:

DKC1; TERT; RTEL1; Dyskeratosis congenita; Next-generation sequencing; Telomere biology disorders,Telomeropathies; Whole-exome sequencing

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