Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China.
Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, People's Republic of China.
BMC Med Genomics. 2018 Jul 16;11(1):60. doi: 10.1186/s12920-018-0377-3.
The proto-oncogene KRAS performs an essential function in normal tissue signaling, and the mutation of KRAS gene is a key step in the development of many cancers. Somatic KRAS mutations are often detected in patients with solid and non-solid tumors, whereas germline KRAS mutations are implicated in patients with the Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome and Costello syndrome. The deletion of chromosome 10q22.3-q23.2 is a rare cytogenetic abnormality, which often leads to distinct facial appearance and delays in speech and global development.
Herein, we report the case of a 4-year-old boy diagnosed with juvenile myelomonocytic leukemia. The boy also had syndromic features, such as speech and motor developmental delay, multiple congenital malformations, including distinct facial features, club feet, and cryptorchidism. Using whole-exome sequencing, we identified a pathogenic mutation in KRAS [c.34G > A, p.Gly12Ser] isolated from peripheral blood DNA. Sanger sequencing confirmed the wild-type sequence in the parents and patient's salivary cell DNA indicating its somatic state. A 7311-kb deletion in 10q22.3-q23.2 was also revealed by chromosomal microarray analysis, which was later proved as a germline de novo variant.
Juvenile myelomonocytic leukemia in the patient was attributed to a somatic KRAS mutation, whereas the syndromic features of the patient were considered a consequence of germline chromosome 10q22.3-q23.2 deletion. Genetic testing for patients with complicated phenotypes can be valuable in detecting multiple pathogenic variants.
原癌基因 KRAS 在正常组织信号传导中发挥着重要作用，KRAS 基因的突变是许多癌症发展的关键步骤。体细胞 KRAS 突变常发生于实体瘤和非实体瘤患者中，而种系 KRAS 突变则与 Noonan 综合征、心面四肢（CFC）综合征和 Costello 综合征患者相关。染色体 10q22.3-q23.2 缺失是一种罕见的细胞遗传学异常，常导致独特的面部外观以及言语和整体发育迟缓。
本研究报道了一例 4 岁男性幼年粒单核细胞白血病患者。该男孩还存在综合征特征，如言语和运动发育迟缓、多种先天性畸形，包括独特的面部特征、马蹄内翻足和隐睾。通过全外显子组测序，我们从外周血 DNA 中鉴定出 KRAS 中的致病性突变[c.34G > A, p.Gly12Ser]。Sanger 测序证实父母和患者唾液细胞 DNA 中存在野生型序列，表明其为体细胞状态。染色体微阵列分析显示 10q22.3-q23.2 存在 7311-kb 缺失，后证实其为种系新生变异。
该患者的幼年粒单核细胞白血病归因于体细胞 KRAS 突变，而患者的综合征特征被认为是种系染色体 10q22.3-q23.2 缺失的结果。对具有复杂表型的患者进行基因检测有助于发现多种致病性变异。
