CLCN7杂合突变常染色体显性遗传石骨症：突变与临床表型分析
1. 前海人寿广州总医院, 内分泌代谢科, 广东广州 511300
2. 广东省第二人民医院, 内分泌科, 广东广州 510220
| 摘 要： | 目的：探讨报道常染色体显性遗传石骨症2型（ADO2）的CLCN7突变与临床表型之间的关系。方法：描述两例患者的临床资料和基因分析结果，结合文献复习，绘制肽链突变位点图谱，总结突变与表型的关系。根据临床表现分为轻型（主要未骨关节痛和偶发骨折）、中型（骨痛、多发骨折，但无造血异常）和重型（在中型基础上出现造血异常）。结果：两例患者一例为男性30岁起病轻型ADO2，仅仅表现为多年的关节疼痛，无骨折；另一例为男性9岁起病，反复骨折并骨痛，重度X线石骨症改变，但没有贫血和脾肿大。基因分析发现突变分别为c.2284C>T（E24）、p.R762W和c.856C>T（E10）、p.R286W。结合文献复习共有42个致病突变报道（含本文新发现的p.R762W），临床表现为轻、中、重型各33.3%、46.7%和20.0%，先证者家系58.8%有单纯突变携带，44.7%有患病家族史。结论：CLCN7杂合突变相关的ADO2，临床表型可覆盖单纯携带、轻型、中型和重型石骨症的广泛谱系。 |
| 关 键 词： | 氯离子通道7基因; 常染色体显性石骨症; 基因突变; 基因型与表型; 突变检测 |
| DOI： | 10.57237/j.wjcm.2022.01.005 |
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收稿日期: 2022-09-06
接受日期: 2022-10-17
在线出版日期: 2022-12-15
Mutation and Phenotype Analysis in Patients with Osteopetrosis Caused by Loss-of-Function Mutation of CLCN7 Single Allele
1. Department of Endocrinology and Metabolism, Foresea Insurance Guangzhou General Hospital, Guangzhou 511300, China
2. Department of Endocrinology, the Second People’s Hospital of Guangdong Province, Guangzhou 510220, China
| Abstract: | Objective: To investigate the relationship between gene mutation and clinical phenotype in patients with autosomal dominant osteopetrosis type 2 (ADO2) caused by single allele mutation of CLCN7. Methods: The two ADO2 cases were clinically described in detail, CLCN7 gene were screened by the next generation sequence assay, and validated by Sanger method. The hazard of mutations was evaluated on PolyPhen2 website. Literature review helped to browse and gather ADO2 cases with CLCN7 data, accordingly all found CLCN7 mutant loci were mapped on the peptide chain, and clinical presentations in each case were tentatively summarized corresponding gene mutation. Phenotype was classified as mild type, intermediate type and severe type according to the degree of clinical presentation. Mild type presents mainly with bone and/or joint pain and occasional bone fracture, intermediate type with additional multiple and recurrent bone fracture, sever type with hematopoietic dysfunction in addition to recurrent bone fractures. Results: The first case was a 30 year old man presenting as mild ADO2 with shorter stature than familial hereditary height, as well as back pain and knee joint pain for up-to nine years. The second case was a 13 year old boy who suffered from recurrent bone fractures since four years ago in addition to short stature and more severe bone pain, but had normal peripheral blood picture. His prominent bone change showed by X-Ray indicated a more typical and severe osteopetrosis than the former. Gene analysis indicated a mutation of c.2284C>T (E24), p.R762W in the first case and c.856C>T (E10), p.R286W in the second case. Literature review gathered 42 pathogenic mutations, mild, intermediate and severe clinical type account for 33.3%, 46.7% and 20.0%, respectively. Among family members of probands, 58.8% had unaffected mutation-carrier, and 44.7% had family history of the disease. Conclusions: In spite of single allele inactivation, CLCN7 related ADO2 may cause highly various clinical phenotype of osteopetrosis, covering normal unaffected, mild, intermediate and severe conditions. The relationship between genotype and phenotype remains obscure in the disease. |
| Keywords: | CLCN7 Gene; Autosomal Dominant Osteopetrosis; Gene Mutation; Genotype and Phenotype; Mutation Detection |
基金
| 1. | 广东省医学科学技术研究基金资助 (A2021005). |
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