Abstract
Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.
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Acknowledgements
We would like to thank all patients and relatives who have participated in the study, and the clinicians who referred samples to our registry. We also thank laboratory assistant Susann Haraldsson for telomere length measurements. Financial support was provided through regional agreement between Umeå University and Västerbotten County Council on cooperation in the field of Medicine, Odontology and Health. SD and MH are supported by grants from the Medical Faculty of Umeå University, the Swedish Childhood Cancer Foundation, Lion's Cancer Research Foundation, Umeå University, the Kempe foundations, and Uppsala-Umeå Comprehensive Cancer Consortium.
Author contributions
Study design: AN, AR, GR, SD, and MH. Data collection: AN, KRJ, LK, YK, PB, JSM, OL, AA, and AOK. Data analysis: AN, AR, PL, and SD. Data interpretation: AN, AR, GR, SD, and MH. Drafting manuscript: AN. All authors revised the manuscript content and approved the final version of the manuscript.
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Norberg, A., Rosén, A., Raaschou-Jensen, K. et al. Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. Eur J Hum Genet 26, 858–867 (2018). https://doi.org/10.1038/s41431-018-0112-8
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DOI: https://doi.org/10.1038/s41431-018-0112-8
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