Functional genomics for curation of variants in telomere biology disorder associated genes, a systematic review

Abstract

AbstractBackgroundPatients with an underlying telomere biology disorder (TBD) have variable clinical presentations and can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatments. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance (VOUS). This complicates management decisions, delays treatment and risks non-uptake of a potentially curative therapies. Improved application of functional genomic evidence may reduce VOUS classifications.MethodsWe systematically searched the literature for published functional assays interrogating TBD gene variants. Where 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.Results3131 articles were screened and 152 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation was available forTERTvariants only. We recommend PS3 and BS3 can be applied at a moderate and supportive level respectively. PS3/BS3 application was limited by a lack of assay standardisation and limited inclusion of benign variants.ConclusionsFurther assay standardisation and assessment of benign variants is required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.