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

Abstract

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 .

Keywords: fetal akinesia deformation sequence; null variant; recurrent pregnancy loss.

Fig. 1. Pedigree (a), clinical profile and variant details of the family with a fetal akinesia deformation sequence.

A large head with dolichocephaly, downs-lanting palpebral fissures, anteverted nares, a small mouth, thin vermilion of the lips and retrognathia, adducted arms with fixed flexion at the elbows, bilateral clenched fists and clinodactyly, adducted thighs, flexion at the hips and knees, bilateral severe talipes equinovarus (b) and pulmonary hypoplasia (white arrow; c) were noted in the fetus (F1 and F2). The variants (V1 and V2) noted in AGRN in the family were as follows: V1: 41.33 kb deletion in chr1:980683–1034219 encompassing exons 1 and 2 of AGRN (paternally inherited; II.1) and V2: NM_198576.4: c.952+1_952+3del p.? in intron 5 (V2 maternally inherited; II.2).