We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11, SOS1, RAF1, LZTR1, and RIT1, detected by Sanger and next‐generation sequencing. The latter was applied to 126 individuals, with a positive yield of 63% in genes of the RAS/MAPK cascade. We present evidence that there are some allelic differences in PTPN11 across distinct populations. We highlight the clinical aspects that pose more medical concerns, such as the cardiac anomalies, bleeding diathesis and proliferative lesions. The genotype–phenotype analysis between the RASopathies showed statistically significant differences in some cardinal features, such as craniofacial and cardiac anomalies, the latter also statistically significant for different genes in Noonan syndrome. We present two individuals with a Noonan syndrome phenotype, one with an atypical, structural cardiac defect, harboring variants in genes mainly associated with isolated hypertrophic cardiomyopathy and discuss the role of these variants in their phenotype.

中文翻译：

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242 例 RAS 病患者的表型-基因型分析：巴西一家三级中心的 18 年经验

我们报告了一个大型队列的临床和分子数据，该队列包括 242 名患有 RAS 病的个体，来自巴西的一个三级中心，这是拉丁美洲最大的研究。Noonan 综合征占受试者的 76%，通过 Sanger 和二代测序检测到9 个不同基因的杂合变异，主要是PTPN11、SOS1、RAF1、LZTR1和RIT1 。后者应用于 126 名个体，RAS/MAPK 级联基因的阳性率为 63%。我们提供的证据表明PTPN11存在一些等位基因差异跨越不同的人群。我们强调引起更多医学问题的临床方面，例如心脏异常、出血素质和增殖性病变。RASopathies 之间的基因型-表型分析显示，在一些主要特征上存在统计学上的显着差异，例如颅面和心脏异常，后者对于 Noonan 综合征的不同基因也具有统计学意义。我们介绍了两个具有 Noonan 综合征表型的个体，一个具有非典型的结构性心脏缺陷，其基因变异主要与孤立的肥厚型心肌病相关，并讨论了这些变异在其表型中的作用。