A Novel Autosomal Recessive Candidate Gene Responsible for RASopathy-Like Phenotype and Bone Marrow Failure: RASA3

IF 0.4 Q4 PEDIATRICS Journal of pediatric genetics Pub Date : 2023-10-26 DOI:10.1055/s-0043-1771526
Akif Ayaz, Zeynep Doğru, Kıvanç Kök, Nihan Bayram, Yöntem Yaman, Abdullah Hüseyin Köseoğlu, Türkan Yiğitbaşı, Aslı Güner Öztürk Demir, Elçin Yüksel, Burcu Dundar, Erdal Fırat Çaralan, Serdar Nepesov, Murat Elli
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Abstract

Abstract 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.
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一种新的常染色体隐性候选基因负责ras病样表型和骨髓衰竭:RASA3
虽然目前已知遗传性骨髓衰竭的许多遗传病因,如Fanconi贫血、Shwachman-Diamond综合征、先天性角化不良症和Diamond-Blackfan贫血,但在这些患者中,很大一部分的致病基因仍然未知。1例6岁女童因发育迟缓、血小板减少症、中性粒细胞减少症和贫血被转至儿科血液科。患者双耳低置,下漏斗胸,咖啡色斑点。在全外显子组分析中,p.K385T (c.1154A >C)检测到RASA3基因的变异为纯合子。该改变的氨基酸位置位于保守有序区域,对应于蛋白质中心的Ras GTPase激活域(Ras- gap)。重要的是,大多数计算机预测致病性的工具预测变异是有害的。RASopathies是一组罕见的遗传病,由Ras-MAPK通路相关基因突变引起,其特征是许多常见的临床表现,如非典型面部特征、生长迟缓和心脏缺陷。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ras病变基因的富集。此外,随后的拓扑聚类揭示了一个假定的功能模块,这进一步表明RASA3在该疾病中是一个新的潜在致病基因。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。相关的,目前的文献也支持我们的发现。总的来说,本研究为RASopathy提供了新的见解,并提出RASA3基因作为该疾病组的新的候选基因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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期刊介绍: The Journal of Pediatric Genetics is an English multidisciplinary peer-reviewed international journal publishing articles on all aspects of genetics in childhood and of the genetics of experimental models. These topics include clinical genetics, molecular genetics, biochemical genetics, medical genetics, dysmorphology, teratology, genetic counselling, genetic engineering, formal genetics, neuropsychiatric genetics, behavioral genetics, community genetics, cytogenetics, hereditary or syndromic cancer genetics, genetic mapping, reproductive genetics, fetal pathology and prenatal diagnosis, multiple congenital anomaly syndromes, and molecular embryology of birth defects. Journal of Pediatric Genetics provides an in-depth update on new subjects and current comprehensive coverage of the latest techniques used in the diagnosis of childhood genetics. Journal of Pediatric Genetics encourages submissions from all authors throughout the world. The following articles will be considered for publication: editorials, original and review articles, short report, rapid communications, case reports, letters to the editor, and book reviews. The aim of the journal is to share and disseminate knowledge between all disciplines in the field of pediatric genetics. This journal is a publication of the World Pediatric Society: http://www.worldpediatricsociety.org/ The Journal of Pediatric Genetics is available in print and online. Articles published ahead of print are available via the eFirst service on the Thieme E-Journals platform.
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