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

TY - JOUR

T1 - Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria

AU - Tometten, Mareike

AU - Kirschner, Martin

AU - Meyer, Robert

AU - Begemann, Matthias

AU - Halfmeyer, Insa

AU - Vieri, Margherita

AU - Kricheldorf, Kim

AU - Maurer, Angela

AU - Platzbecker, Uwe

AU - Radsak, Markus

AU - Schafhausen, Philippe

AU - Corbacioglu, Selim

AU - Höchsmann, Britta

AU - Matthias Wilk, C

AU - Hinze, Claas

AU - Chromik, Jörg

AU - Heuser, Michael

AU - Kreuter, Michael

AU - Koschmieder, Steffen

AU - Panse, Jens

AU - Isfort, Susanne

AU - Kurth, Ingo

AU - Brümmendorf, Tim H

AU - Beier, Fabian

N1 - Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

U2 - 10.1097/HS9.0000000000000874

DO - 10.1097/HS9.0000000000000874

M3 - SCORING: Journal article

C2 - 37096215

VL - 7

SP - e874

JO - HEMASPHERE

JF - HEMASPHERE

SN - 2572-9241

IS - 5

ER -