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.