停經前痛風關節炎患者的痛風相關基因全外顯子定序分析

Whole Exome Sequencing of Gout Related Genes in Patients with Premenopausal Gouty Arthritis

目的：探索停經前痛風患者，帶有痛風易感基因的變異點位（missense variant）的角色。方法：2019年至2020年期間，門診收案5名無血緣關係的停經前痛風關節炎患者，進行了全外顯子定序。在17個痛風和高尿酸血症的相關基因中，找尋變異點位。少見變異定義為在臺灣生物資料庫或千人基因組資料庫中，次要等位基因頻率小於0.01。使用SIFT，PolyPhen2和CADD等電腦模擬工具來預測胺基酸改變的效應，變異點位的臨床解釋符合美國醫學遺傳學暨基因體學學會（ACMG, American College of Medical Genetics and Genomics）與分子病理學學會（AMP, Association for Molecular Pathology）的臨床指引。結果：在兩名患者中分別發現ABCG2基因上的少見變異D128V和F491L。60%的患者，在ABCG2基因攜帶相同的常見變異點位Q141K。高尿酸血症相關的單基因遺傳病的基因中，未發現致病性或可能的致病性變異（HPRT1、PRPS1、UMOD、G6PC、AGL、SLC37A4、PFKM、PYGM、CPT2、ALDOB、AMDP1和ACADS）。結論：本研究顯示ABCG2的變異點位，在停經前痛風關節炎仍然扮演一定的角色，且未來還需要進一步的功能測試或性狀共分離（co-segregation）研究。

Objectives: To explore the role of missense variants in gout susceptibility genes in patients with premenopausal gouty arthritis Methods: We performed whole exome sequencing in five unrelated patients with premenopausal gouty arthritis from an outpatient clinic between 2019 and 2020. We searched for missense variants in 17 gout and hyperuricemia-related genes. Rare variant was defined as minor allele frequency less than 0.01, using the Taiwan Biobank or 1000 Genomes databases. We performed in silico functional predictions using SIFT, PolyPhen2 and CADD, all of which characterized the amino acid change effects. The clinical interpretation of genetic variants was based on the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP). Results: Two rare missense variants, D128V and F491L, in ABCG2 were identified in two patients. Three out of five patients carried the same common variant (Q141K) in ABCG2. No pathogenic or potentially pathogenic variant was identified in the genes of monogenic inheritance diseases which were associated with hyperuricemia (HPRT1, PRPS1, UMOD, G6PC, AGL, SLC37A4, PFKM, PYGM, CPT2, ALDOB, AMDP1, and ACADS). Conclusions: In this study, we suggest that ABCG2 is still a concern in premenopausal gouty arthritis. Further functional assays or co-segregation studies are needed.