Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing
Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing
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DOI：
10.1038/gim.2016.220
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发表时间：
2017-09-01
影响因子：
8.8
通讯作者：
Riviere, Jean-Baptiste
中科院分区：
文献类型：
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作者：
Kuentz, Paul;St-Onge, Judith;Riviere, Jean-Baptiste
目的：PIK3CA的合子后激活突变引起广泛的花叶病，统称为PIK3CA相关过度生长谱（PROS）。我们描述了PIK3CA测序在PROS中的诊断率和特征。方法：我们对162例临床实验室患者的各种组织进行了PIK3CA的超深下一代测序（NGS），并通过表型和组织检测评估诊断率。结果：我们在66.7%（108/162）的患者中发现了致病突变，突变等位基因水平低至1%。症候群的诊断率（74%）高于孤立病例（35.5%），P = 9.03 × 10（-5）。我们鉴定了40种不同的突变，发现强致癌突变在无脑过度生长的患者中（50.6%）比脑过度生长的患者（15.2%,P = 0.00055）更频繁。无论表型如何，皮肤和过度生长组织中的突变等位基因水平高于血液和口腔样本（P = 3.9 x 10(-25)）。结论：我们的数据证明了超深层NGS在PROS分子诊断中的价值，突出了其大量的等位基因异质性，并证实了最佳诊断需要来自患处的新鲜皮肤或手术样本。我们的发现可能对今后推荐PROS和其他花叶病的基因检测具有指导价值。
Purpose: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS.Methods: We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested.Results: We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 x 10(-5)). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 x 10(-25)), regardless of the phenotype.Conclusion: Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.