Biallelic variants in AGRN in a family with recurrent pregnancy losses and fetal akinesia deformation sequence

Introduction 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. Methods 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. Results Perinatal phenotyping revealed 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. Conclusion 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.