Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity
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DOI：
10.1038/gim.2014.205
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发表时间：
2015-11-01
影响因子：
8.8
通讯作者：
Rehm, Heidi L.
中科院分区：
文献类型：
--
作者：
Alfares, Ahmed A.;Kelly, Melissa A.;Rehm, Heidi L.
目的：肥厚性心肌病（HCM）主要由编码肌节蛋白的基因的致病变异引起。我们报告了10年来广泛转诊人群中2,912名无亲缘关系且无综合征表现的HCM基因检测结果。方法：2004 - 2007年采用Sanger测序对10个基因进行基因检测，2007 - 2011年采用HCM CardioChip对11个基因进行基因检测，2011年起采用下一代测序对18、46、51个基因进行基因检测。结果：未选择先证者的检出率为32%，另有15%的未确定结果。成人先证者与儿童先证者的检出率无显著差异，但女性检出率高于男性。一个包含50多个基因的扩展基因小组只发现了非常少的致病变异，而在我们最初的小组中发现了11个基因。691名高危家庭成员的家族基因检测消除了纵向心脏评估的需要。根据美国心脏病学会基金会/美国心脏协会推荐的HCM家族成员临床评估的医疗保险费用表的预计成本，我们的数据表明，基因检测至少节省了约70万美元的成本。结论：临床HCM基因检测为许多患者提供了明确的分子诊断，并为家庭节省了费用。扩大的基因组并没有实质性地增加HCM检测的临床敏感性，这表明HCM的主要其他原因仍有待确定。
Purpose: Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years.Methods: Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward.Results: The detection rate is similar to 32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million.Conclusion: Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.