Novel variants in Nordic patients referred for genetic testing of telomere-related disorders

Anna Norberg*, Anna Rosén, Klas Raaschou-Jensen, Lars Kjeldsen, Jukka S. Moilanen, Ylva Paulsson-Karlsson, Panagiotis Baliakas, Olli Lohi, Aymen Ahmed, Astrid O. Kittang, Pär Larsson, Göran Roos, Sofie Degerman, Magnus Hultdin

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalEuropean Journal of Human Genetics
Volume26
Issue number6
Pages (from-to)858–867
ISSN1018-4813
DOIs
Publication statusPublished - Jun 2018

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Telomere
Telomere Shortening
Virulence
DNA

Keywords

  • Adolescent
  • Adult
  • Aged
  • Cell Cycle Proteins/genetics
  • Child
  • Child, Preschool
  • Dyskeratosis Congenita/genetics
  • Female
  • Genetic Testing
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins/genetics
  • RNA/genetics
  • Telomerase/genetics
  • Telomere Shortening/genetics
  • Telomere-Binding Proteins/genetics
  • Telomere/genetics
  • Young Adult

Cite this

Norberg, Anna ; Rosén, Anna ; Raaschou-Jensen, Klas ; Kjeldsen, Lars ; Moilanen, Jukka S. ; Paulsson-Karlsson, Ylva ; Baliakas, Panagiotis ; Lohi, Olli ; Ahmed, Aymen ; Kittang, Astrid O. ; Larsson, Pär ; Roos, Göran ; Degerman, Sofie ; Hultdin, Magnus. / Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. In: European Journal of Human Genetics. 2018 ; Vol. 26, No. 6. pp. 858–867.
@article{c525ea84d5c342aca5572fbbe0131e59,
title = "Novel variants in Nordic patients referred for genetic testing of telomere-related disorders",
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.",
keywords = "Adolescent, Adult, Aged, Cell Cycle Proteins/genetics, Child, Child, Preschool, Dyskeratosis Congenita/genetics, Female, Genetic Testing, Humans, Infant, Male, Middle Aged, Mutation, Nuclear Proteins/genetics, RNA/genetics, Telomerase/genetics, Telomere Shortening/genetics, Telomere-Binding Proteins/genetics, Telomere/genetics, Young Adult",
author = "Anna Norberg and Anna Ros{\'e}n and Klas Raaschou-Jensen and Lars Kjeldsen and Moilanen, {Jukka S.} and Ylva Paulsson-Karlsson and Panagiotis Baliakas and Olli Lohi and Aymen Ahmed and Kittang, {Astrid O.} and P{\"a}r Larsson and G{\"o}ran Roos and Sofie Degerman and Magnus Hultdin",
year = "2018",
month = "6",
doi = "10.1038/s41431-018-0112-8",
language = "English",
volume = "26",
pages = "858–867",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",
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Norberg, A, Rosén, A, Raaschou-Jensen, K, Kjeldsen, L, Moilanen, JS, Paulsson-Karlsson, Y, Baliakas, P, Lohi, O, Ahmed, A, Kittang, AO, Larsson, P, Roos, G, Degerman, S & Hultdin, M 2018, 'Novel variants in Nordic patients referred for genetic testing of telomere-related disorders', European Journal of Human Genetics, vol. 26, no. 6, pp. 858–867. https://doi.org/10.1038/s41431-018-0112-8

Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. / Norberg, Anna; Rosén, Anna; Raaschou-Jensen, Klas; Kjeldsen, Lars; Moilanen, Jukka S.; Paulsson-Karlsson, Ylva; Baliakas, Panagiotis; Lohi, Olli; Ahmed, Aymen; Kittang, Astrid O.; Larsson, Pär; Roos, Göran; Degerman, Sofie; Hultdin, Magnus.

In: European Journal of Human Genetics, Vol. 26, No. 6, 06.2018, p. 858–867.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Novel variants in Nordic patients referred for genetic testing of telomere-related disorders

AU - Norberg, Anna

AU - Rosén, Anna

AU - Raaschou-Jensen, Klas

AU - Kjeldsen, Lars

AU - Moilanen, Jukka S.

AU - Paulsson-Karlsson, Ylva

AU - Baliakas, Panagiotis

AU - Lohi, Olli

AU - Ahmed, Aymen

AU - Kittang, Astrid O.

AU - Larsson, Pär

AU - Roos, Göran

AU - Degerman, Sofie

AU - Hultdin, Magnus

PY - 2018/6

Y1 - 2018/6

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Cell Cycle Proteins/genetics

KW - Child

KW - Child, Preschool

KW - Dyskeratosis Congenita/genetics

KW - Female

KW - Genetic Testing

KW - Humans

KW - Infant

KW - Male

KW - Middle Aged

KW - Mutation

KW - Nuclear Proteins/genetics

KW - RNA/genetics

KW - Telomerase/genetics

KW - Telomere Shortening/genetics

KW - Telomere-Binding Proteins/genetics

KW - Telomere/genetics

KW - Young Adult

U2 - 10.1038/s41431-018-0112-8

DO - 10.1038/s41431-018-0112-8

M3 - Journal article

C2 - 29483670

AN - SCOPUS:85042538231

VL - 26

SP - 858

EP - 867

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 6

ER -