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Molecular diagnosis in a cohort of 114 patients with rare skeletal dysplasias
American Journal of Medical Genetics Seminars in Medical Genetics, Part C ( IF 3.1 ) Pub Date : 2021-09-16 , DOI: 10.1002/ajmg.c.31937
Karina C Silveira 1 , Thatiane Y Kanazawa 1 , Cynthia Silveira 1 , Maria D J Lacarrubba-Flores 1 , Benilton S Carvalho 2 , Denise P Cavalcanti 1
Affiliation  

Molecular diagnosis is important to provide accurate genetic counseling of skeletal dysplasias (SD). Although next-generation sequencing (NGS) techniques are currently the preferred methods for analyzing these conditions, some of the published results have not shown a detection rate as high as it would be expected. The present study aimed to assess the diagnostic yield of targeted NGS combined with Sanger sequencing (SS) for low-coverage exons of genes of interest and exome sequencing (ES) in a series of patients with rare SD and use two patients as an example of our strategy. This study used two different in-house panels. Of 93 variants found in 88/114 (77%) patients, 57 are novel. The pathogenic variants found in the following genes: B3GALT6, PCYT1A, INPPL1, LIFR, of four patients were only detected by SS. In conclusion, the high diagnostic yield reached in the present study can be attributed to both a good selection of patients and the utilization of the SS for the insufficiently covered regions. Additionally, the two case reports—a patient with acrodysostosis related to PRKAR1A and another with ciliopathy associated with KIAA0753, add new and relevant clinical information to the current knowledge.

中文翻译:

114 例罕见骨骼发育不良患者队列的分子诊断

分子诊断对于提供骨骼发育不良 (SD) 的准确遗传咨询很重要。尽管新一代测序 (NGS) 技术目前是分析这些条件的首选方法,但一些已发表的结果并未显示出像预期的那样高的检测率。本研究旨在评估靶向 NGS 结合 Sanger 测序 (SS) 对一系列罕见 SD 患者的低覆盖率外显子和外显子测序 (ES) 的诊断率,并以两名患者为例我们的战略。本研究使用了两种不同的内部面板。在 88/114 (77%) 患者中发现的 93 种变异中,有 57 种是新的。在以下基因中发现的致病变异:B3GALT6PCYT1A4 名患者的INPPL1LIFR仅被 SS 检测到。总之,本研究中达到的高诊断率可归因于对患者的良好选择和对未充分覆盖区域的 SS 的利用。此外,这两个病例报告,带acrodysostosis与患者PRKAR1A和另一个与相关ciliopathy KIAA0753,添加新的和相关的临床信息,以目前的知识。
更新日期:2021-09-24
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