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Functional genomics for curation of variants in telomere biology disorder associated genes: A systematic review


Nelson, N and Feurstein, S and Niaz, N and Truong, J and Holien, JK and Lucas, S and Fairfax, K and Dickinson, J and Bryan, TM, Functional genomics for curation of variants in telomere biology disorder associated genes: A systematic review, Genetics in Medicine, 25, (3) pp. 1-18. ISSN 1098-3600 (2023) [Refereed Article]

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DOI: doi:10.1016/j.gim.2022.11.021


Purpose: Patients with an underlying telomere biology disorder (TBD) have variable clinical presentations, and they can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatment. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance. This complicates management decisions, delays treatment, and risks nonuptake of potentially curative therapies. Improved application of functional genomic evidence may reduce variants of uncertain significance classifications.

Methods: We systematically searched the literature for published functional assays interrogating TBD gene variants. When possible, established likely benign/benign and likely pathogenic/pathogenic variants were used to estimate the assay sensitivity, specificity, positive predictive value, negative predictive value, and odds of pathogenicity.

Results: In total, 3131 articles were screened and 151 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation were available for TERT variants only. We recommend that PS3 and BS3 can be applied at a moderate and supportive level, respectively. PS3/BS3 application was limited by a lack of assay standardization and limited inclusion of benign variants.

Conclusion: Further assay standardization and assessment of benign variants are required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.

Item Details

Item Type:Refereed Article
Keywords:telomere biology disorders, medical genetics, haematology, pulmonary fibrosis
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer genetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Nelson, N (Dr Niles Nelson)
UTAS Author:Lucas, S (Dr Sionne Lucas)
UTAS Author:Fairfax, K (Dr Kirsten Fairfax)
UTAS Author:Dickinson, J (Professor Joanne Dickinson)
ID Code:154996
Year Published:2023
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-01-23
Last Modified:2023-01-23

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