虽然许多遗传病因,比如范可尼贫血,Shwachman-Diamond综合征,先天性角化障碍,和Diamond-Blackfan贫血,遗传性骨髓衰竭是今天已知的,这些患者中很大一部分的负责基因仍然未知。一个6岁的女孩,他们的父母是堂兄,由于生长迟缓被转诊到儿科血液科,血小板减少症,中性粒细胞减少症,和贫血。病人的耳朵很低,漏斗胸下部,和咖啡斑点。在全外显子组分析中,检测到RASA3基因中的p.K385T(c.1154A>C)变体为纯合的。改变的氨基酸位置位于保守且有序的区域,对应于蛋白质中心的RasGTP酶激活域(Ras-GAP)。重要的是,大多数致病性的计算机预测工具预测变异体具有破坏性。放射病,其特点是许多常见的临床发现,例如非典型的面部特征,增长延迟,和心脏缺陷,是一组由Ras-MAPK通路中涉及的基因突变引起的罕见遗传疾病。该患者的发现与RASopathy样表型和骨髓衰竭一致。有趣的是,在RASA3蛋白-蛋白相互作用网络中观察到RASopathy基因的富集。此外,随后的拓扑聚类揭示了一个假定的功能模块,这进一步暗示RASA3在这种疾病中作为一种新的潜在致病基因。在这种情况下,检测到的RASA3突变可能通过破坏RASA3蛋白与其相互作用伙伴之间的功能合作而在临床上表现为观察到的表型.相关地,目前的文献也支持所获得的发现。总的来说,这项研究提供了对RASopathy的新见解,并提出RASA3基因作为该疾病组的新候选基因。
Although many genetic etiologies, such as Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, and Diamond-Blackfan anemia, from hereditary bone marrow failure are known today, the responsible gene remains unknown in a significant part of these patients. A 6-year-old girl, whose parents were first-cousin consanguineous, was referred to the pediatric hematology department due to growth retardation, thrombocytopenia, neutropenia, and anemia. The patient had low-set ears, pectus excavatum inferiorly, and cafe-au-lait spots. In whole-exome analysis, p.K385T (c.1154A > C) variant in the RASA3 gene was detected as homozygous. The amino acid position of the alteration is located in the conserved and ordered region, corresponding to the Ras GTPase activation domain (Ras-GAP) in the center of the protein. Importantly, most of in silico prediction tools of pathogenicity predicts the variant as damaging. RASopathies, which are characterized by many common clinical findings, such as atypical facial features, growth delays, and heart defects, are a group of rare genetic diseases caused by mutations in the genes involved in the Ras-MAPK pathway. The findings in this patient were consistent with the
RASopathy-like phenotype and bone marrow failure. Interestingly, enrichment of
RASopathy genes was observed in the RASA3 protein-protein interaction network. Furthermore, the subsequent topological clustering revealed a putative function module, which further implicates RASA3 in this disease as a novel potential causative gene. In this context, the detected RASA3 mutation could be manifesting itself clinically as the observed phenotype by disrupting the functional cooperation between the RASA3 protein and its interaction partners. Relatedly, current literature also supports the obtained findings. Overall, this study provides new insights into
RASopathy and put forward the RASA3 gene as a novel candidate gene for this disease group.