Folkhälsan Research Center, Helsinki, Finland.
Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
J Neuromuscul Dis. 2020;7(2):153-166. doi: 10.3233/JND-190423.
Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.
To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants.
We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort.
We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified.
We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.
广泛的基因筛查会导致数千种罕见变异的鉴定，这些变异很难解释。由于肌联蛋白（TTN）基因的罕见变异非常大，在任何个体中都经常会被检测到。在许多患有肌肉疾病或心肌病的患者中，对分子发现的明确解释几乎是不可能的。
完善与 TTN 相关的骨骼肌疾病的现行分类框架，并规范 TTN 变异的解读。
我们使用美国医学遗传学与基因组学学院（ACMG）和分子病理学协会（AMP）发布的指南，重新分析了我们患者队列中的 TTN 遗传发现。
我们在分类指南中发现了三条不适用于与 TTN 相关的骨骼肌疾病的规则；六条需要针对疾病/基因进行特定调整的规则和四条需要定量阈值才能正确使用的规则。在三种情况下，规则强度需要修改。
我们建议对指南进行调整。我们提供频率阈值，以方便筛选候选致病变异，并为功能数据和共分离证据的使用和解释提供指导。我们期望随着对这些疾病的进一步了解，TTN 相关骨骼肌疾病的变异分类框架将得到进一步完善。
