1例女性杜氏肌营养不良的分子遗传学机制

doi:10.6040/j.issn.1671-7554.0.2023.0199

摘要/Abstract

摘要： 目的探究1例女性Duchenne型肌营养不良患儿的临床表型及基因变异特点,并分析其分子遗传学发病机制。方法对1例女性杜氏肌营养不良患儿的进行临床评估、肌肉活检病理分析,应用多重连接探针扩增技术(MLPA)和Ion Torrent半导体测序检测患儿的DMD基因,并对其父母进行家系验证,进行染色体核型分析和运用微阵列比较基因组杂交(a-CGH)检测患儿染色体变异情况,采用人雄激素受体基因甲基化特异性PCR(HUMARA-MSP)对患儿进行X染色体失活模式的检测。结果患儿为女性,就诊时3岁,主要表现为肌酸激酶(CK)增高和运动能力稍差,肌肉病理示肌营养不良样改变和抗肌萎缩蛋白的缺失。MLPA技术未检测出患儿存在DMD基因的缺失突变或重复突变,Ion Torrent半导体测序结果发现患儿DMD基因存在c.10223+1G>A单一杂合突变,且该突变为新发突变。患儿染色体核型正常,a-CGH未检测到染色体异常。HUMARA-MSP证实患儿存在明显的X染色体失活偏移。结论该女性患儿携带DMD基因c.10223+1G>A单一杂合突变,X染色体失活偏移是导致该女性DMD患儿的发病原因。

关键词: 杜氏肌营养不良症, X染色体失活, 人雄激素受体基因甲基化特异性PCR, 女性

Abstract: Objective To explore the clinical phenotypes and gene variation characteristics of a female child with Duchenne muscular dystrophy, and to explore its molecular genetic pathogenesis. Methods Clinical data and muscle biopsy of the child were analyzed. Multiplex ligation-dependent probe amplification(MLPA)and Ion Torrent amplicon sequencing were performed to detect variants in the DMD gene of the child and her parents. Karyotype analysis and array-based comparative genomic hybridization(a-CGH)were carried out for the detection of chromosome variations. In addition, human androgen receptor gene methylation-specific PCR(HUMARA-MSP)was conducted to identify the X chromosome inactivation skewing. Results The patient was three years old at the first visit. The main clinical symptoms were increased creatine kinase(CK)level and reduced athletic capacity. Muscle pathology showed myodystrophic changes and loss of dystrophin protein. MLPA did not detect deletion and duplication mutations in the DMD gene. Ion Torrent amplicon sequencing revealed heterozygous c.10223 + 1G>A in the DMD gene, a spontaneous mutation. Chromosome karyotypes were normal, and a-CGH did not detect chromosomal abnormalities. Significant X chromosome inactivation skewing in this patient was confirmed by HUMARA-MSP. Conclusion The child carried a heterozygous c.10223+1G>A in the DMD gene, and the X chromosome inactivation skewing was the cause of DMD.

Key words: Duchenne muscular dystrophy, X chromosome inactivation, Human androgen-receptor gene methylation-specific PCR, Female

中图分类号:

R746.2

吴文静,孙媛,王光裕,吕晓晴,焉传祝,林鹏飞. 1例女性杜氏肌营养不良的分子遗传学机制[J]. 山东大学学报 (医学版), 2023, 61(10): 95-100.

WU Wenjing, SUN Yuan, WANG Guangyu, LYU Xiaoqing, YAN Chuanzhu, LIN Pengfei. Molecular genetic mechanism of Duchenne muscular dystrophy in a female case[J]. Journal of Shandong University (Health Sciences), 2023, 61(10): 95-100.

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