Figure Titles and Captions
Figure 1: Uncharacterized gene reporting and reclassification workflow
Figure 1: Up until 2020, uncharacterized gene analysis was performed for informative trios with an uncertain or negative result following characterized gene analysis. Currently, uncharacterized genes are analyzed for negative cases or for probands where the identified characterized gene finding only accounts for part their phenotype (‘partial overlap’). Genes are continually evaluated based on the latest literature to determine if the published evidence is sufficient to characterize the gene-disease association. Once characterized, all previously reported DES cases with rare variants in a gene are assessed for clinical overlap and proactive reclassification reports are issued to appropriate cases. Our laboratory has several workflows are addressing uncertain results for reclassification. New gene characterizations result in our highest rate of reclassifications. Participation in data-sharing initiatives include GeneMatcher, ClinVar, the Undiagnosed Disease Network, and collaborations established directly with investigators. Only gene and variant information are shared on these platforms with follow-up clinical details provided on a case-by-case basis. Ordering clinicians are contacted for a promising lead and connected to collaborators for additional data sharing and patient consent to participate in publications or additional studies. Other efforts for reclassification include performing reanalysis by clinician request and implementing bioinformatic pipeline upgrades and other technology upgrades, both of which are largely time-dependent. Family studies and additional lab studies (i.e. RNA analysis, structural modeling) are variant-dependent and to date not widely available for most alterations.
Figure 2: Overall impact of gene characterization following GeneMatcher entry
Figure 2: 480 characterized gene reports were issued as of October 2021 for gene-disease associations entered in GeneMatcher. In total, 219 (45.63%) of these were reclassifications proactively issued by the laboratory. 109 of these reports were upgraded reclassifications from candidate gene reports, and 110 were reclassifications issued to individuals who did not initially meet our candidate gene reporting criteria. After establishing a gene-disease association, 261 additional probands received a relevant finding in one of these genes, illustrating the impact disease gene discoveries have on the overall DES diagnostic rate. For 79 cases for which we issued a candidate gene report, the gene-disease association remains uncharacterized. In 4 cases, further review of a reported candidate gene no longer met our criteria. These findings were removed from the proband’s report, and reclassifications were issued. Additionally, these matches were marked as ‘suspended’ in GeneMatcher. Currently, we have 4 cases pending review for reclassification based on literature published this year.
Figure 3: Co-authored peer-reviewed publications
Figure 3: Since 2013, we have co-authored 105 peer-reviewed papers describing gene-disease associations. These included descriptions of 104 unique genes. 4 genes (BPTF, FDXR, IQSEC2 , and SON ) were the topic of more than one paper. A comprehensive list of these publications can be found in supplement Table 2.