Purpose

The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity.

Methods

Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized.

Results

Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families.

Conclusion

We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.

中文翻译：

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临床对治疗的反应在确定基因组变异的致病性中的作用

目的

2015 年美国医学遗传学和基因组学/分子病理学协会 (ACMG/AMP) 序列变异解释指南提供了一个框架，用于标准化通过基因检测发现的变异分类中的术语。我们的目的是评估利用针对疑似疾病的治疗的临床反应来阐明变异致病性的有效性。

方法

总结了在多种诊断环境中评估和治疗的具有不同临床表现和不同遗传疾病的五个家庭。

结果

扩展评估表明可能的基因诊断和分配的候选因果变异，但在每个实例中累积的临床、生化和分子信息与已识别的疾病并不完全一致。针对受影响个体的疑似诊断开始治疗，导致所有五个家庭的临床改善。

结论

我们建议，针对可治疗遗传疾病的特异性和靶向疗法的效果体现了体内生理反应，并且可以被视为 2015 年 ACMG/AMP 指南中确定基因组变异致病性的附加标准。