3 | RESULTS
In total, 246 candidate entries representing 243 unique genes were
submitted to GeneMatcher from our laboratory between March 2016 and
September 2021 [Supplement Table 1]. Four gene entries (EIF2C,
ITGA11, LRFN2, and UNC45B ) were subsequently marked as
‘suspended’ because they no longer met candidate gene criteria per our
laboratory’s GDV scoring metric. Of note, one of these genes,UNC45B was subsequently characterized for an autosomal dominant
congenital myopathy in December 2020; however, we had originally
submitted as an autosomal recessive cause of Joubert syndrome with
skeletal and ocular anomalies. There were three genes (ANK3,
RYR3, and SPTBN4 ) that each had two entries representing
distinct phenotypes of interest including differences in inheritance
models or suspected mechanism of disease.
As of October 2021, 45.93% of entries have been characterized [Table
1]. Most candidate gene entries were for autosomal dominant de
novo occurrences; however, there are no significant differences for
characterization based on zygosity, inheritance pattern or alterations
type. Of the 246 entries, 153 (62.20%) had at least one case with a
reported uncharacterized gene finding, meaning the gene, variant,
proband combination met candidate gene reporting criteria described in
Farwell Hagman, et al. (2017). Submissions that had at least one case
meeting our candidate criteria were significantly more likely to be
characterized (79/153; 51.63%) as of October 2021 compared to genes
with no candidates meeting reporting criteria (34/93; 36.56%; p=0.025).
In total, 196 probands received a candidate gene report involving one of
the genes entered in GeneMatcher. Of these, 32 genes had more than one
uncharacterized report [range 2-4]. Currently, 480 probands received
a reportable finding after the gene was characterized, which accounts
for 11.96% (480/4012) of all characterized gene reports from our
laboratory (data not shown). Of these 480 cases, 219 (45.63%) were
reclassifications of an original result [Figure 2].
Reclassifications include upgrades from candidate gene results
(uncertain) or the addition of the finding to a previous report. 75
genes had more than one reported characterized case [range of 2-31].
Our laboratory has co-authored 105 peer-reviewed papers describing
gene-disease associations for 104 unique genes between 2013 and 2021
[Supplement Table 2]. 39.42% (41/104) of these genes were
candidates we had submitted to GeneMatcher. Majority of publications
were the initial description of a gene-disease association, but also
follow-up publications that further defined rare Mendelian disorders
[Figure 3].