Combined Histological and Proteomic Analysis Reveals Muscle Denervation in KMT5B-Related Neurodevelopmental Disorder: A Case Report

Background: Patients with neurodevelopmental and neuromuscular disorders often show overlapping clinical phenotypes. Pathogenic variants in KMT5B, a histone lysine methyltransferase, have been linked to neurodevelopmental disorders, yet their effects on human skeletal muscle remain unexplored. We report a patient with KMT5B-linked disease who presented to a neuromuscular specialty clinic with significant involvement of skeletal muscle, where a multi-omics approach established the genetic diagnosis and revealed neuromuscular findings relevant for diagnosis, care and rehabilitation. Methods: Whole-exome sequencing was performed from blood and data was analyzed using the RD-Connect Genome Phenome Analysis Platform. Histological analysis and proteomic profiling were performed on muscle tissue. Results: Whole-exome sequencing revealed a pathogenic heterozygous variant (c.554_557del, p.Tyr185Cysfs*27) in KMT5B. Histological examination revealed fiber-type grouping, angular fibers, increased fast-twitch fiber proportion, and lipid droplet accumulation, indicative of muscle denervation. Proteomic profiling identified 77 dysregulated proteins, including upregulation of sarcomeric proteins, mitochondrial and glycolytic enzymes, acute-phase and complement factors, and extracellular matrix components, reflecting structural remodeling, metabolic adaptation, and inflammatory activation. These findings align with phenotypes observed in Kmt5b mouse models, supporting a role of KMT5B in neuromuscular function.

研究背景：神经发育与神经肌肉疾病患者常表现出重叠的临床表型。组蛋白赖氨酸甲基转移酶（histone lysine methyltransferase）KMT5B的致病变异已被证实与神经发育障碍相关，但其对人类骨骼肌的影响尚未得到探究。本文报道一例KMT5B相关疾病患者，该患者因骨骼肌显著受累就诊于神经肌肉专科门诊，研究团队通过多组学方法明确了该患者的遗传学诊断，并揭示了与诊断、治疗及康复相关的神经肌肉表型特征。研究方法：采集患者血液样本开展全外显子测序（Whole-exome sequencing），测序数据通过RD-Connect基因组表型组分析平台进行分析；对获取的患者肌肉组织开展组织学分析与蛋白质组谱分析（proteomic profiling）。研究结果：全外显子测序显示，KMT5B基因存在一处致病性杂合变异（c.554_557del，p.Tyr185Cysfs*27）。组织学检查可见肌纤维型分组、角状肌纤维、快缩肌纤维比例升高及脂滴蓄积，提示肌肉存在去神经支配改变。蛋白质组谱分析共鉴定出77个表达异常的蛋白质，包括肌节蛋白、线粒体与糖酵解酶、急性期反应蛋白及补体因子、细胞外基质成分的上调表达，上述改变反映了肌肉的结构重塑、代谢适应及炎症激活状态。本研究结果与Kmt5b小鼠模型中观测到的表型相符，进一步佐证了KMT5B在神经肌肉功能中的重要作用。