Systematic reanalysis of genomic data improves quality of variant interpretation

Abstract

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

RNA‐Seq detects a SAMD12‐EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas

“…While the proband is unaffected by myoclonus, it could be hypothesized that the mechanistically distinct, mosaic loss-of-function observed in this case could elicit a unique effect with relevance the observed phenotype. Ultimately however, either functional validation studies or further patient-based analyses are necessary to draw any conclusion and SAMD12 represents a gene whose functional links should be flagged for future systematic reanalysis (Hiatt et al, 2018;Wenger, Guturu, Bernstein, & Bejerano, 2017). A further consideration is the clinically reported 16p13.3 deletion and corresponding detection of a PDPK1-PRSS21 fusion transcript.…”

Next‐generation sequencing approaches and challenges in the diagnosis of developmental anomalies and intellectual disability

“…In spite of these difficulties, pioneer studies have showed the interest of srGS as a diagnostic tool in DA/ID, resulting in a positive yield of around 30% in individuals with previous negative ES results or as a first-line molecular test. [41][42][43] As for ES, periodic reanalysis of srGS data, in light of new scientific knowledge, will further increase diagnostic rate (~10%) [44][45][46] in clinical settings is to be restricted to Mendelian disease-causing genes. 15 Therefore, it is crucial to keep any bioinformatics pipeline upto-date with the available literature.…”

Ethical considerations for modern molecular pathology

“…Genetic alterations of which the clinical significance is still unclear today may be classified in the future as definitely pathogenic or benign. The possibility of reanalysis is a big advantage of DNA sequencing, maximizing its benefit for clinical care . Current literature on (whether, and to what extent there is an obligation for) genetic reanalysis is focused on the CG context using WES/WGS.…”

“…benefit for clinical care [68,69] . Current literature on (whether, and to what extent there is an obligation for) genetic reanalysis is focused on the CG context using WES/WGS.…”