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

Autor: Minna Koskenvuo, Kirsi Jahnukainen, Jean-Laurent Casanova, Sofie Degerman, Ulla Wartiovaara-Kautto, Timi Martelius, Anna Norberg, Janna Saarela, Luca Trotta, Mervi Taskinen, Mikko Seppänen, Vivien Béziat, Hannamari Välimaa
Přispěvatelé: Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Oncology, Hematologian yksikkö, Medicum, Department of Virology, Oral and Maxillofacial Surgery, Doctoral Programme in Clinical Research, Department of Medicine, Infektiosairauksien yksikkö, Doctoral Programme in Integrative Life Science, Janna Saarela / Principal Investigator, HUS Children and Adolescents, HUS Comprehensive Cancer Center
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Telomerase
Telomere biology disorders
DYSKERATOSIS-CONGENITA
lcsh:Medicine
Hoyeraal-Hreidarsson syndrome
VARIANTS
dyskeratosis congenita
Bioinformatics
MOLECULAR-GENETICS
whole-exome quencing
0302 clinical medicine
Locus heterogeneity
Pharmacology (medical)
Child
Genetics (clinical)
Exome sequencing
Telomeropathies
General Medicine
Telomere
READ ALIGNMENT
Pedigree
3. Good health
telomeropathies
Child
Preschool
030220 oncology & carcinogenesis
Whole-exome sequencing
Medical genetics
Female
Telomere biology disorders
Telomeropathies
Dyskeratosis congenita
Medical Genetics
Adult
medicine.medical_specialty
TERT
Young Adult
03 medical and health sciences
Rare Diseases
BURROWS-WHEELER TRANSFORM
Molecular genetics
Exome Sequencing
medicine
Humans
Medicinsk genetik
MUTATIONS
business.industry
Research
DKC1
RTEL1
lcsh:R
HOYERAAL-HREIDARSSON SYNDROME
DNA Helicases
medicine.disease
Human genetics
030104 developmental biology
3121 General medicine
internal medicine and other clinical medicine
Mutation
Next-generation sequencing
next-generation sequencing
3111 Biomedicine
business
telomere biology disorders
Zdroj: Orphanet Journal of Rare Diseases, Vol 13, Iss 1, Pp 1-9 (2018)
Orphanet Journal of Rare Diseases
ISSN: 1750-1172
DOI: 10.1186/s13023-018-0864-9
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s13023-018-0864-9) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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