3rd Department of Pediatrics, University of Athens, Medical School, University General Hospital "ATTIKON", Chaidari, Greece.
Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Eur J Pediatr. 2022 Oct;181(10):3691-3700. doi: 10.1007/s00431-022-04574-w. Epub 2022 Jul 29.
Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, known as Rasopathies, due to the implication of genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease's recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and next-generation sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are as follows: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype-phenotype analysis showed statistically significant differences in craniofacial dysmorphisms (p = 0.005) and pulmonary valve stenosis (PS) (p < 0.001) frequencies between patients harbouring a pathogenic variant and patients without pathogenic variant in any of the tested genes. Patients with at least a pathogenic variant had 6.71 times greater odds to develop PS compared to pathogenic variant-negative patients (OR = 6.71, 95%; CI = (2.61, 17.27)). PTPN11 positive patients showed higher frequency of epicanthal folds (p = 0.004), ptosis (p = 0.001) and coarseness (p = 0.001) and lower frequency of neurological findings (p = 0.006), compared to patients carrying pathogenic variants in other genes.
Craniofacial dysmorphism and PS prevail among pathogenic variant positive compared to pathogenic variant negative NS and NS-like patients while neurological defects are less common in PTPN11-affected NS patients compared to patients harbouring pathogenic variants in other genes. The significant prevalence of the Ras/MAPK pathogenic variants (17.4%), other than PTPN11, in Greek NS patients, highlights the necessity of a wider spectrum of molecular diagnosis.
• Noonan syndrome (NS) has been associated with pathogenic variants in molecules-components of the Ras/MAPK pathway. • Clinical and genetic description of NS patients worldwide helps establishing personalized monitoring.
• NS and NS-like mutational rate in Greece reaches 50% with pathogenic variants identified mostly in PTPN11 (32.5%), RIT1 (6%) and SOS1 (4.7%) genes. • The risk for pulmonary stenosis increases 6.71-fold in NS patients with a pathogenic variant compared to patients without genetic alterations.
努南综合征（NS）是一种常染色体显性遗传疾病，具有临床和遗传异质性。它属于更广泛的 Ras 通路疾病组，因为涉及编码 Ras/MAPK 信号通路成分的基因。在不同人群中记录遗传改变有助于评估特定基因的特定特征，这对于更好地识别、预测和监测疾病至关重要。在此，我们报告了在希腊雅典的一家三级中心接受治疗的 86 名 NS 或 NS 样患者的临床和分子数据。分析使用 Sanger 和下一代测序技术，包含 14 个不同的基因。在希腊 NS 人群中，已确认的 NS 相关基因的突变率如下：PTPN11（32.5%）、RIT1（5.8%）、SOS1（4.7%）、BRAF（1.2%）、CBL（1.2%）、KRAS（1.2%）、MAP2K1（1.2%）、RAF1（1.2%）、SHOC2（1.2%），总 NS 人群阳性率为 50%。基因型-表型分析显示，在颅面畸形（p=0.005）和肺动脉瓣狭窄（PS）（p<0.001）频率方面，携带致病性变异的患者与任何检测基因均无致病性变异的患者之间存在统计学显著差异。与致病性变异阴性患者相比，至少携带一种致病性变异的患者发生 PS 的几率高 6.71 倍（OR=6.71，95%；CI=（2.61,17.27））。与携带其他基因致病性变异的患者相比，PTPN11 阳性患者的内眦赘皮（p=0.004）、上睑下垂（p=0.001）和粗糙（p=0.001）的频率更高，而神经系统发现（p=0.006）的频率更低。
与致病性变异阴性的 NS 和 NS 样患者相比，致病性变异阳性的患者颅面畸形和 PS 更为常见，而 PTPN11 受累的 NS 患者的神经缺陷较少。在希腊 NS 患者中，Ras/MAPK 致病性变异（除 PTPN11 外，还有 17.4%）的显著流行，强调了更广泛的分子诊断的必要性。
•努南综合征（NS）与 Ras/MAPK 通路分子的致病性变异有关。•全球 NS 患者的临床和遗传描述有助于建立个性化监测。
•在希腊，NS 和 NS 样的突变率达到 50%，致病性变异主要发生在 PTPN11（32.5%）、RIT1（6%）和 SOS1（4.7%）基因中。•与无遗传改变的患者相比，携带致病性变异的 NS 患者发生 PS 的风险增加 6.71 倍。
