Shravya Mangalore S, Chaurasia Ankur, Girisha Katta M, Nayak Shalini S
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Clin Dysmorphol. 2025 Jan 10;34(2):25-31. doi: 10.1097/MCD.0000000000000517.
Agrin, encoded by AGRN, plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS.
We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants.
Perinatal phenotyping revealed an FADS in the family, and genomic testing identified novel null variants in AGRN. First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1_952+3del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN.
This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN.
由AGRN基因编码的聚集蛋白在乙酰胆碱受体聚集途径中起着至关重要的作用，已知该途径中的任何缺陷都会在儿童早期导致先天性肌无力综合征（CMS）8，并伴有不同程度的易疲劳性肌肉无力。CMS最严重或致命的形式表现为胎儿运动不能变形序列（FADS）。迄今为止，仅有一个家族报道了AGRN基因的无效变异与致命性FADS有关。
我们鉴定出一对非近亲结婚且反复流产的夫妇。通过围产期尸检对胎儿进行详细的表型分析。进行基因评估并结合拆分读段分析以鉴定变异。
围产期表型分析显示该家族存在FADS，基因组检测鉴定出AGRN基因中的新型无效变异。首先，全外显子组测序揭示胎儿中存在母系遗传的AGRN基因杂合变异c.952+1_952+3del。对外显子组的拆分读段分析导致鉴定出父系遗传的第二个变异，即一个41.33 kb的杂合缺失，涵盖AGRN基因的第1和第2外显子。
本研究强调了在临床实践中纳入拆分读段分析的重要性，并强调了AGRN基因无效变异与FADS之间的关联。据我们所知，这是解释FADS与AGRN基因无效变异的第二篇报道。
