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].