1] Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. [2] Perdana University Graduate School of Medicine, Serdang, Malaysia. [3] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.
Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
致病基因的等位基因异质性对将基因组变异转化为临床实践提出了重大挑战。囊性纤维化跨膜电导调节因子 (CFTR) 基因中的近 2000 个变体中，只有少数具有导致囊性纤维化的经验证据。为了解决这一差距，我们收集了北美和欧洲登记处和诊所中 39696 名囊性纤维化患者的基因型和表型数据。在这些个体中，159 种 CFTR 变体的等位基因频率为 ł0.01%。对这些变体进行了临床严重程度和功能后果的评估，其中 127 种（80%）符合疾病的临床和功能标准。对 2188 名囊性纤维化个体的父亲进行疾病外显率评估，使 12 种剩余的 32 种变体中的 12 种被归为中性，而其他 20 种变体仍不确定其影响。这项研究表明，直接从表型良好的个体中获取数据可以解决我们解释临床相关基因组变异的能力差距。
