Wong Lee-Jun C, Chen Ting, Schmitt Eric S, Wang Jing, Tang Sha, Landsverk Megan, Li Fangyuan, Zhang Shulin, Wang Yue, Zhang Victor W, Craigen William J
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Baylor Genetics Laboratory, Houston, Texas.
Hum Mutat. 2020 Oct;41(10):1783-1796. doi: 10.1002/humu.24082. Epub 2020 Jul 22.
Interpretation of mitochondrial protein-encoding (mt-mRNA) variants has been challenging due to mitochondrial characteristics that have not been addressed by American College of Medical Genetics and Genomics guidelines. We developed criteria for the interpretation of mt-mRNA variants via literature review of reported variants, tested and refined these criteria by using our new cases, followed by interpreting 421 novel variants in our clinical database using these verified criteria. A total of 32 of 56 previously reported pathogenic (P) variants had convincing evidence for pathogenicity. These variants are either null variants, well-known disease-causing variants, or have robust functional data or strong phenotypic correlation with heteroplasmy levels. Based on our criteria, 65.7% (730/1,111) of variants of unknown significance (VUS) were reclassified as benign (B) or likely benign (LB), and one variant was scored as likely pathogenic (LP). Furthermore, using our criteria we classified 2, 12, and 23 as P, LP, and LB, respectively, among 421 novel variants. The remaining stayed as VUS (91.2%). Appropriate interpretation of mt-mRNA variants is the basis for clinical diagnosis and genetic counseling. Mutation type, heteroplasmy levels in different tissues of the probands and matrilineal relatives, in silico predictions, population data, as well as functional studies are key points for pathogenicity assessments.
由于美国医学遗传学与基因组学学会指南未涉及的线粒体特征，线粒体蛋白质编码（mt - mRNA）变异的解读一直具有挑战性。我们通过对已报道变异的文献综述制定了mt - mRNA变异解读标准，利用新病例对这些标准进行测试和完善，随后使用这些经过验证的标准对我们临床数据库中的421个新变异进行解读。在先前报道的56个致病性（P）变异中，共有32个具有令人信服的致病性证据。这些变异要么是无效变异、已知致病变异，要么具有可靠的功能数据或与异质性水平有很强的表型相关性。根据我们的标准，65.7%（730/1111）意义未明变异（VUS）被重新分类为良性（B）或可能良性（LB），1个变异被评为可能致病（LP）。此外，使用我们的标准，在421个新变异中，我们分别将2个、12个和23个分类为P、LP和LB。其余的仍为VUS（91.2%）。对mt - mRNA变异进行恰当解读是临床诊断和遗传咨询的基础。突变类型、先证者及母系亲属不同组织中的异质性水平、计算机预测、群体数据以及功能研究是致病性评估的关键点。
