RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype–phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.

RASopathies 是由编码 RAS/MAPK 信号通路组分或调节剂的基因变异引起的。Noonan 综合征是这组疾病中最常见的实体，其特征是心脏缺陷、身材矮小、发育迟缓和典型的面部特征。最近在 Noonan 综合征患者中发现了SOS2 中的杂合变异，编码 RAS 的鸟嘌呤核苷酸交换因子。已发表的SOS2相关 Noonan 综合征病例数量仍然有限，而且对基因型-表型相关性知之甚少。我们从 17 名携带致病SOS2 的个体中收集了先前未发表的临床和基因型数据变体。大多数个体具有先前报告的显性致病变异之一；只有四个在影响蛋白质功能的变体的既定热点上发生了新的变化。17 名患者的整体表型非常符合 Noonan 综合征的谱系，与SOS1相关 Noonan 综合征患者中观察到的表型最相似，外胚层异常是共同特征，身材矮小和学习障碍是相对罕见的发现。平均努南综合征表型。SOS2 中的心脏缺陷谱相关的 Noonan 综合征与 RASopathies 中已知的心脏异常谱一致，但没有特别占优势的特定心脏缺陷。值得注意的是，淋巴异常异常频繁，影响了超过一半的患者。因此，我们得出结论，与SOS2相关的 Noonan 综合征与淋巴并发症的风险特别高，这可能对发病率和生活质量产生重大影响。