Abstract
Purpose :
Current knowledge about the genetic componnets of thyroid eye disease (TED) is limited. In this study, we aimed to identify de novo variants implicated in TED using whole-exome sequencing in trios of euthyroid Graves' ophthalmopathy (EGO), a specific subtype of TED.
Methods :
We performed whole-exome sequencing in 7 EGO trios, each having one proband with EGO and both unaffected parents. We annoted all de novo variants in the probands, i.e., variants only occurred in the probands but not in their parents. We only kept single nucleotide variants (SNV) and indels with an allelic frequency <0.002 in one database among 1000 Genome project, exome sequencing project, and ExAC database.
Results :
Totally 82 de novo SNVs among the 7 trios were identified. Notably, SNVs detected in more than 1 trio were found in 6 genes: FLG, FCGBP, PCDHB3, PCDHB4, PCDHB11 and RBMXL1. SNVs were detected in 4 genes with functions likely related to cellular infiltration of TED: XCL2, FAM160A2, MUC17 and MT1G. Two SNVs were detected in PRAMEF4 and ALDH1A2 which are related to the pathway of retinoic acid metabolism. We also detected 6 deletions and 9 insertions after filtering. One deletion in the NACAD gene occurred in 2 trios.
Conclusions :
In this study, we have identified more than 10 novel candidate genes for EGO. Functions of some of these genes indicated possible involvements of cellular infiltration and retinoic acid matabolic pathways in TED. Further validation of these genes in a larger patient cohort is ongoing.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.