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When phenotype does not match genotype: importance of "real-time" refining of phenotypic information for exome data interpretation.
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-08-17 , DOI: 10.1038/s41436-020-00938-5
Lina Basel-Salmon 1, 2, 3, 4 , Noa Ruhrman-Shahar 1 , Naama Orenstein 2 , Yael Goldberg 1, 3 , Claudia Gonzaga-Jauregui 5 , Alan R Shuldiner 5 , Rivka Sukenik-Halevy 1, 3 , Idit Maya 1 , Nurit Magal 1 , Ofir Hagari 1 , Noy Azulay 1 , Gabriel Arie Lidzbarsky 1 , Lily Bazak 1
Affiliation  

Purpose

Clinical data provided to genetic testing laboratories are frequently scarce. Our purpose was to evaluate clinical scenarios where phenotypic refinement in proband’s family members might impact exome data interpretation.

Methods

Of 614 exomes, 209 were diagnostic and included in this study. Phenotypic information was gathered by the variant interpretation team from genetic counseling letters and images. If a discrepancy between reported clinical findings and presumably disease-causing variant segregation was observed, referring clinicians were contacted for phenotypic clarification.

Results

In 16/209 (7.7%) cases, phenotypic refinement was important due to (1) lack of cosegregation of disease-causing variant with the reported phenotype; (2) identification of different disorders with overlapping symptoms in the same family; (3) similar features in proband and family members, but molecular cause identified in proband only; and (4) previously unrecognized maternal condition causative of child’s phenotype. As a result of phenotypic clarification, in 12/16 (75%) cases definition of affected versus unaffected status in one of the family members has changed, and in one case variant classification has changed.

Conclusion

Detailed description of phenotypes in family members including differences in clinical presentations, even if subtle, are important in exome interpretation and should be communicated to the variant interpretation team.



中文翻译:

当表型与基因型不匹配时:“实时”精炼表型信息对于外显子组数据解释的重要性。

目的

提供给基因检测实验室的临床数据通常很少。我们的目的是评估先证者家庭成员的表型细化可能影响外显子组数据解释的临床情况。

方法

在 614 个外显子组中,有 209 个具有诊断性并被纳入本研究。变异解释团队从遗传咨询信件和图像中收集表型信息。如果观察到报告的临床发现与可能导致疾病的变异分离之间存在差异,则联系转诊临床医生以澄清表型。

结果

在 16/209 (7.7%) 的病例中,表型细化很重要,因为 (1) 致病变异与报告的表型缺乏共同分离;(2) 识别同一家族中具有重叠症状的不同疾病;(3) 先证者和家庭成员的特征相似,但仅在先证者中发现了分子原因;(4) 以前未发现的导致儿童表型的母体状况。作为表型澄清的结果,在 12/16 (75%) 的病例中,其中一名家庭成员的受影响与未受影响状态的定义发生了变化,其中一个病例的变异分类发生了变化。

结论

家庭成员表型的详细描述,包括临床表现的差异,即使是细微的,在外显子组解释中也很重要,应该传达给变异解释团队。

更新日期:2020-08-17
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