Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss-of-function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain-of-function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.

中文翻译：

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神经纤维瘤病的临床变异性 1：同时发生的 PTPN11 变体和非典型脑 MRI 发现的改变作用

神经纤维瘤病 1 (NF1) 是一种疾病，其特征在于由NF1中的功能丧失变异体引起的可变表达性，编码神经纤维蛋白，一种负性控制 RAS 信号传导的蛋白质。我们评估了与神经纤维蛋白功能相关的蛋白质的并发变异是否有助于 NF1 的可变表达。对 138 名经分子证实临床诊断为 NF1 的个体的 RASopathy 基因组进行平行测序，确定了PTPN11中的错义变异，在来自三个无关家庭的四名受试者中编码 SHP2，一种 RAS 信号的正调节剂。三名受试者是功能获得性变体的杂合子，并表现出严重的 NF1 表达（发育迟缓、多发性脑肿瘤和特殊的皮质 MRI 发现），并且具有类似于 Noonan 综合征（由PTPN11中的激活变体引起的 RASopathy ）的特征。相反，第四位受试者表现出减弱的表现，携带先前未报告的PTPN11变体，该变体在体外具有亚形态行为。我们的发现记录了功能相关的PTPN11变异发生在一小部分但显着比例的 NF1 调节疾病表现的受试者中，这表明致病性NF1变异的临床表达通过伴随与神经纤维蛋白功能相关的蛋白质的失调而改变。我们还建议将 SHP2 功能作为治疗 NF1 进化并发症的一种方法。