Akif Ayaz, Zeynep Do��ru, K��van�� K��k, Nihan Bayram, Y��ntem Yaman, Abdullah H��seyin K��seo��lu, T��rkan Yi��itba����, Asl�� G��ner ��zt��rk Demir, El��in Y��ksel, Burcu Dundar, Erdal F��rat ��aralan, Serdar Nepesov, Murat Elli
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 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 protein-protein interaction network. Furthermore, the subsequent topological clustering revealed a putative function module, which further implicates in this disease as a novel potential causative gene. In this context, the detected mutation could be manifesting itself clinically as the observed phenotype by disrupting the functional cooperation between the 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 gene as a novel candidate gene for this disease group.
