Veracity Neuroscience LLC, Memphis, Tennessee, US.
University of Memphis, Memphis, Tennessee, US.
Tremor Other Hyperkinet Mov (N Y). 2020 Nov 4;10:50. doi: 10.5334/tohm.567.
Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in , a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of -linked M-D is unknown, the pathogenicity of variants identified in patients with M-D may be indeterminant, and variants predicted to be deleterious by analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies.
variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated pathogenic variants.
Within gnomAD v2, there were 56, 408, and 1250 alleles harboring variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an variant with a CADD score ≥ 25.
M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees.
analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.
肌阵挛 - 肌张力障碍（M-D）是一种具有可变外显率的多效性神经精神疾病。在母系印迹基因 中，致病性变异是 M-D 最常见的已知遗传原因。 - 连锁 M-D 的人群患病率未知，在 M-D 患者中鉴定出的致病性 变异可能不确定，并且通过 分析预测为有害的 变异可能出现在因看似无关的疾病而接受外显子组或全基因组测序的患者中。基因组聚集数据库（gnomAD）v2 提供了来自 125748 个外显子组和 15708 个基因组的变异数据，这些个体是作为各种疾病特异性和群体遗传学研究的一部分进行测序的无关个体。
使用综合注释依赖耗竭（CADD）和非同义单核苷酸多态性功能预测数据库（dbNSFP）分析 gnomAD v2 数据集内的变异。我们确定了 gnomAD v2 数据集内按有害性评分排序的注释 变异的频率。将有害性评分与一组已发表的与疾病相关的致病性 变异进行比较。
在 gnomAD v2 中，分别有 56、408 和 1250 个等位基因携带 CADD 评分大于 30、25 和 20 的 变异。我们估计，在美国人群中，大约有 1/348 的个体携带 CADD 评分≥25 的 变异。
由于多效性、轻度表型、可变外显率和获得遗传检测的机会有限，M-D 可能被误诊。由于有害的 变异的高人群患病率，在没有共分离分析和对家系内表型进行专家神经学检查的情况下，断言致病性时应谨慎。
对大型遗传变异人群数据库的分析表明，美国有超过 0.2%的个体携带高度有害的 变异。这一发现表明，M-D 和轻度孤立性肌阵挛等轻微表型变异可能被误诊。
