Null variants in AGRN cause lethal fetal akinesia deformation sequence

Abstract

We present a case of lethal fetal akinesia deformation sequence (FADS) caused by a frameshift variant in trans with a 148 kbp deletion encompassing 3‐36 exons of AGRN. Pathogenic variants in AGRN have been described in families with a form of congenital myasthenic syndrome (CMS), manifesting in the early childhood with variable fatigable muscle weakness. To the best of our knowledge, this is the first case of FADS caused by defects in AGRN gene. FADS has been reported to be caused by pathogenic variants in genes previously associated with CMS including these involved in endplate development and maintenance: MuSK, DOK7, and RAPSN. FADS seems to be the most severe form of CMS. None of the reported in the literature CMS cases associated with AGRN had two null variants, like the case presented herein. This indicates a strong genotype‐phenotype correlation.

Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes

“…4 heterozygous de novo variants were detected in four fetuses. The de novo variant (MYH3:c.2501T > C; p.Phe834Ser) was novel (Figure S1) whilst the other 3 variants in PTPN11, FGFR3, and FOXF1 have been reported previously (Abu-El-Haija et al 2018; Rump et al 2006; Stankiewicz et al 2009; Tartaglia et al 2004; Toydemir et al 2006).Along with the abnormal USS ndings, the molecular genetic ndings in this study may support the pathogenicity of the following genes: AGRN(Geremek et al 2020), MPDZ (Saugier-Veber et al 2017), IL6ST(Schwerd et al 2017), TBC1D32 (Alsahan and Alkuraya 2020), CANT1(Laccone et al 2011), FZD6(Shamseldin et al 2015) and TMEM94 (Al-Hamed et al 2020) as etiologies of fetal structural anomalies.Our data also supports previous ndings of an association of biallelic NEK8 mutations with a multisystem ciliopathy phenotype (Al-Hamed et al 2016;Frank et al 2013). The fetus FAM-53, with a homozygous nonsense mutation in NEK8 had multisystem features consistent with a ciliopathy syndrome which included hypoplastic lung, Dandy-Walker malformation and enlarged cystic-dysplastic kidneys.There were several instances where the phenotype we report extends the clinical disease spectrum associated with a known gene alterations.…”

Agrin-Mediated Cardiac Regeneration: Some Open Questions

“…Agrin knockout in mice results in death at birth, but no gross histological abnormalities have been recorded in cardiac tissues (Gautam et al, 1996;Burgess et al, 2000). Similar findings have been described for the only human case reported of an agrinnull variant leading to perinatal death, (Geremek et al, 2020). Such evidence strongly indicates that agrin is not essential for CM proliferation during embryogenesis.…”

Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes

“…Along with the abnormal USS ndings, the molecular genetic ndings in this study may support the pathogenicity of the following genes: AGRN(Geremek et al 2020), MPDZ (Saugier-Veber et al 2017), IL6ST(Schwerd et al 2017), TBC1D32 (Alsahan and Alkuraya 2020), CANT1(Laccone et al 2011), FZD6(Shamseldin et al 2015) and TMEM94 (Al-Hamed et al 2020) as etiologies of fetal structural anomalies.Our data also supports previous ndings of an association of biallelic NEK8 mutations with a multisystem ciliopathy phenotype(Al-Hamed et al 2016;Frank et al 2013). The fetus FAM-53, with a homozygous nonsense mutation in NEK8 had multisystem features consistent with a ciliopathy syndrome which included hypoplastic lung, Dandy-Walker malformation and enlarged cystic-dysplastic kidneys.There were several instances where the phenotype we report extends the clinical disease spectrum associated with a known gene alterations.…”