Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Am J Med Genet A. 2021 Dec;185(12):3623-3633. doi: 10.1002/ajmg.a.62410. Epub 2021 Jun 29.
RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.
RAS 病是一组由 Ras/丝裂原活化蛋白激酶通路基因编码的致病性变异引起的疾病，具有重叠的临床和分子特征。本研究旨在描述 38 例 RAS 病患者的临床和分子特征。对相关基因进行 Sanger 或靶向下一代测序，以及 NF1 的多重连接依赖性探针扩增分析。致病性变异检测率为 94.4%。在 18 例 Noonan 综合征（NS）患者中，PTPN11 导致了 50%，SOS1、LZTR1、RIT1 和 RAF1 分别导致了其余的 27.8%、11.1%、5.5%和 5.5%。LZTR1 中的三个变异是新的，其中两个在一名智力残疾和肥厚型心肌病患者的复合杂合状态中被鉴定，而第三个变异在一名肺动脉瓣狭窄和智力正常的患者中被发现为杂合状态。我们描述了 SOS1、RIT1 和 RAF1 变异患者的幽门狭窄、膝关节脱位和腭裂，这些以前没有报道过。我们在来自同一 NS 家系的三个患者中检测到 PTPN11 变异。BRAF 和 MAP2K2 变异在 8 例 Cardiofaciocutaneous 综合征患者中被发现。在 2 例 Costello 综合征患者中检测到 2 种 HRAS 变异，其中 1 例为轻度，另 1 例为重度。在 4 例伴有智力残疾的神经纤维瘤病-NS 患者中鉴定出 NF1 大片段缺失，而在 1 例具有错义变异的患者中，智力正常。总之，本研究提供了 LZTR1 中的三个新变异，并扩展了罕见 RAS 病的临床表型。
