基于胚系 NF1 变异体鉴定和 NF1 及非 NF1 先天性胫骨假关节的特征：75 例患者的遗传和临床分析。
Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients.
机构信息
Department of Pediatric Orthopaedics, Hunan Children's Hospital, The Pediatric Academy of the University of South China, 86# Ziyuan Road, Changsha, Hunan Province, 410007, People's Republic of China.
Pediatrics Research Institute of Hunan Province, Hunan Children's Hospital, 86 Ziyuan Road, Changsha, Hunan Province, People's Republic of China.
出版信息
Orphanet J Rare Dis. 2019 Sep 18;14(1):221. doi: 10.1186/s13023-019-1196-0.
BACKGROUND
Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients.
RESULTS
Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery.
CONCLUSIONS
We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.
背景
先天性胫骨假关节（CPT）是一种罕见疾病。一些患者表现出神经纤维瘤病 1 型（NF1），而另一些患者则没有表现出 NF1（非 NF1）。CPT 的病因，特别是非 NF1 CPT 的病因，尚不清楚。在这里，我们对 75 例 CPT 病例的种系变体进行了筛查，包括 55 例 NF1 和 20 例非 NF1。根据 NF1 基因突变对临床数据进行分类和分析，以研究两种类型患者的基因型-表型关系。
结果
使用全外显子组测序和多重连接依赖性探针扩增，55 例 NF1 CPT 患者中有 44 例（80.0%）被鉴定为携带 NF1 基因突变。25 个变体是新的；53.5%的变体是从头出现的，与携带遗传变异的携带者相比，其携带者发生骨折的比例更高。在所有 20 例非 NF1 患者中均未发现 NF1 致病变异。NF1 CPT 与非 NF1 CPT 的临床特征比较，在弯曲或骨折发病、侧化、组织病理结果、胫骨近端骨骺异常以及手术后胫骨愈合的随访方面，没有显著差异。非 NF1 患者中相当大比例的存在囊性病变（Crawford Ⅲ型），并且在手术后使用支架。
结论
我们分析了大量非 NF1 和 NF1 CPT 患者，并为与种系 NF1 变体相关的基因型-表型特征提供了新的视角。一般来说，非 NF1 CPT 的胫骨临床特征与 NF1 CPT 相似。种系 NF1 致病变异可将 NF1 与非 NF1 CPT 区分开来，但不能解释 NF1 患者 CPT 的异质性。我们的结果表明，非 NF1 CPT 可能不是由种系 NF1 致病变异引起的。除 NF1 外，其他遗传变异也可能导致 CPT 发病。我们的研究结果将有助于 NF1 致病变异在 CPT 遗传咨询中的解释。
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