Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria

Mareike Tometten; Martin Kirschner; Robert Meyer; Matthias Begemann; Insa Halfmeyer; Margherita Vieri; Kim Kricheldorf; Angela Maurer; Uwe Platzbecker; Markus Radsak; Philippe Schafhausen; Selim Corbacioglu; Britta Höchsmann; C Matthias Wilk; Claas Hinze; Jörg Chromik; Michael Heuser; Michael Kreuter; Steffen Koschmieder; Jens Panse; Susanne Isfort; Ingo Kurth; Tim H Brümmendorf; Fabian Beier

doi:10.1097/HS9.0000000000000874

Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria

Hemasphere. 2023 Apr 20;7(5):e874. doi: 10.1097/HS9.0000000000000874. eCollection 2023 May.

Authors

Mareike Tometten^{1

2}, Martin Kirschner^{1

2}, Robert Meyer^{2

3}, Matthias Begemann^{2

3}, Insa Halfmeyer^{1

2}, Margherita Vieri^{1

2}, Kim Kricheldorf^{1

2}, Angela Maurer^{1

2}, Uwe Platzbecker⁴, Markus Radsak⁵, Philippe Schafhausen⁶, Selim Corbacioglu⁷, Britta Höchsmann^{8

9}, C Matthias Wilk¹⁰, Claas Hinze¹¹, Jörg Chromik¹², Michael Heuser¹³, Michael Kreuter^{14

15}, Steffen Koschmieder^{1

2}, Jens Panse^{1

2}, Susanne Isfort^{1

2}, Ingo Kurth^{2

3}, Tim H Brümmendorf^{1

2}, Fabian Beier^{1

2}

Affiliations

¹ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
² Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
³ Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany.
⁴ Clinic for Hematology, Cellular Therapy, and Hemostaseology, University Hospital Leipzig, Germany.
⁵ Department of Hematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁶ Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Regensburg, Germany.
⁸ Institute of Transfusion Medicine and Immunogenetics, University of Ulm, Germany.
⁹ Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Germany.
¹⁰ Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Switzerland.
¹¹ Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Germany.
¹² Department of Medicine, Hematology and Oncology, Goethe-University, Frankfurt, Germany.
¹³ Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
¹⁴ Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany.
¹⁵ Academic Center for Pulmonary Medicine, Departments of Pneumology, Mainz University Medical Center, and of Pulmonary, Critical Care & Sleep Medicine, Marienhaus Clinic Mainz, Germany.

Abstract

Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in TERT and TERC. In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.