Unidade de Genética, Instituto da Criança do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):896-911. doi: 10.1002/ajmg.c.31851. Epub 2020 Oct 31.
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.
我们报告了一个由 242 名 RASopathy 患者组成的大队列的临床和分子数据，这些患者均来自巴西的一家三级中心，这是拉丁美洲最大的研究。其中，Noonan 综合征占 76%，存在九个不同基因（主要为 PTPN11、SOS1、RAF1、LZTR1 和 RIT1）的杂合变异，这些变异通过桑格测序和下一代测序检测到。对 126 名患者进行了后者的检测，在 RAS/MAPK 级联的基因中阳性检出率为 63%。我们提供了证据表明，不同人群中 PTPN11 存在一些等位基因差异。我们强调了具有更多医学关注的临床方面，例如心脏异常、出血倾向和增生性病变。RASopathy 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显著差异，例如颅面和心脏异常，后者在 Noonan 综合征的不同基因中也具有统计学显著差异。我们介绍了两个具有 Noonan 综合征表型的个体，其中一个具有非典型的结构性心脏缺陷，携带与孤立性肥厚型心肌病主要相关的基因变异，并讨论了这些变异在其表型中的作用。
