由IGHMBP2突变引起的常染色体隐性遗传性Charcot-Marie-Tooth病2S型(AR-CMT2S)于2014年首次报道,并且在过去的八年中报告了越来越多的病例。我们使用Sanger测序和下一代测序(NGS)在我们的178个中国CMT2家族中的8个典型AR-CMT2S家族中检测到15个不同的IGHMBP2突变,使IGHMBP2突变成为我们队列中AR-CMT2的最常见原因。从2014年到2022年,34个AR-CMT2S家族,包括45名患者和47种不同的突变,被报道。三分之一的已鉴定突变代表假定的功能丧失变体(无义,移码和拼接),而三分之二是错义变化,聚集在解旋酶和ATPase结构域中。发病年龄为0.11岁至20岁(平均±SD:3.76±3.93岁),婴儿(0-2岁)发病组患者最多(51.1%)。最初的症状包括肌肉无力(15,33.3%),延迟的里程碑(9%,20%),足畸形(8,17.8%),步态障碍(8,17.8%),英尺下降(7,15.6%),频繁下跌(3.6.7%),肌张力减退(2,4.4%)和鱼际萎缩(1,2.2%)。用PyMOL软件对26个错义IGHMBP2突变进行分子结构模型分析,发现6个突变接近RNA结合通道,8个突变在核苷酸结合口袋中或附近.根据现有有限的临床资料,位于或接近这些基序的错义变化似乎可能与更严重的临床结局有关.总之,IGHMBP2突变筛查应推荐用于早期发作,中度或严重影响,和散发性或AR-CMT2患者。少数患者发病相对较晚,病情较轻,在基因诊断和治疗中应该给予更多的关注。虽然我们的初步分析表明错义突变的定位与临床表现之间存在潜在的联系,基因型-表型关系的定义将需要来自更多系列患者的统一临床信息.
Autosomal recessive Charcot-Marie-Tooth disease Type 2S (AR-CMT2S) caused by
IGHMBP2 mutation was first reported in 2014, and an increasing number of cases have been reported in the past eight years. We detected 15 distinct
IGHMBP2 mutations among 8 typical AR-CMT2S families in our cohort of 178 Chinese CMT2 families using Sanger sequencing and next-generation sequencing (NGS), making
IGHMBP2 mutations the most frequent cause of AR-CMT2 in our cohort. From 2014 to 2022, 34 AR-CMT2S families, including 45 patients and 47 different mutations, were reported. One third of identified mutations represented presumed loss-of-function variants (nonsense, frameshift and splicing), while two-thirds were missense changes which clustered in the helicase and ATPase domains. The age at onset ranged from 0.11 years to 20 years (mean±SD: 3.76±3.93 years) and the infantile (0-2 years) onset group accounted for the most patients (51.1%). The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%). Molecular structural model analysis of 26 missense
IGHMBP2 mutations using PyMOL software revealed that six mutations were close to the RNA-binding channel, eight mutations were in or close to the nucleotide-binding pocket. Based on available limited clinical information, it seems possible that missense changes located in or close to these motifs might be linked to a more severe clinical outcome. In conclusion,
IGHMBP2 mutation screening should recommended for early-onset, moderately or severely affected, and sporadic or AR-CMT2 patients. A tiny minority of patients were relatively late onset and mild affected, which should be given more attention in genetic diagnosis and treatment. While our preliminary analysis suggests a potential link between the localization of missense mutations and clinical presentation, definition of genotype-phenotype relationships will require harmonized clinical information from a larger series of patients.