Functional validation of TERT and TERC variants of uncertain significance in patients with short telomere syndromes

Ferrer, Alejandro; Mangaonkar, Abhishek A.; Stroik, Susanna; Zimmermann, Michael T.; Sigafoos, Ashley N.; Kamath, Patrick S.; Simonetto, Douglas A.; Wylam, Mark E.; Carmona, Eva M.; Lazaridis, Konstantinos N.; Peters, Steve G.; Stewart, Keith; Klee, Eric W.; Hendrickson, Eric A.; Patnaik, Mrinal M.

doi:10.1038/s41408-020-00386-z

Cited by 3 publications

(5 citation statements)

References 14 publications

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Section: Discussionmentioning

confidence: 99%

“…The NGS panel was established on the basis of the standard established in 2017, so recently discovered genes in this highly dynamic field of research were not yet investigated 45 . In addition, follow‐up functional studies could help to better classify and probably categorize VUS findings into pathogenic/likely pathogenic, although functional assays are not available for nearly half of TBD‐associated variants indicating the need for further investigation 38,41 …”

Section: Discussionmentioning

confidence: 99%

“…However, we detected additional 7 VUS in this extended screening group in addition to the 17 VUS in the standard screening cohort. Similar findings regarding VUS were reported by Ferrer et al 38 who had 31% with VUS in a cohort of 32 patients with suspected TBD. By using 3D molecular modeling and functional assays, they were able to reclassify 5 VUS identified patients into the pathogenic/likely pathogenic group.…”

Section: Discussionmentioning

confidence: 99%

“…45 In addition, follow-up functional studies could help to better classify and probably categorize VUS findings into pathogenic/ likely pathogenic, although functional assays are not available for nearly half of TBD-associated variants indicating the need for further investigation. 38,41 The screening algorithm evaluated here restricted the performance of NGS to the subpopulation of patients with abnormal TL. As stated above, it needs to be pointed out that also in case of TL >10th percentile and even in cases with elongated TL, a residual possibility for an underlying TBD and thereby a diagnostic gap remains.…”

Section: Aq7mentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Aq7mentioning

confidence: 99%

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

et al. 2023

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“…Genetic testing was performed using either an in-house research-based whole exome sequencing (WES) or commercial bone marrow failure-specific targeted next generation sequencing (NGS) panel or exome-based customized panels (ES-Slices) (Supplementary table 1 ). Whole-exome sequencing (WES) was performed at the Clinical Genomics Laboratory (Mayo Clinic) using a previously published protocol [ 12 , 13 ]. Genomic data was processed through an in-house bioinformatics pipeline and analyzed by the Translational Omics Program at the Center for Individualized Medicine (Mayo Clinic) using Emedgene analysis software (Emedgene Technologies).…”

mentioning

confidence: 99%