Mutations in the NEB gene cause fetal akinesia/arthrogryposis multiplex congenita

Objective We studied a series of patients with fetal akinesia deformation sequence (FADS)/arthrogryposis multiplex congenita (AMC), with nemaline bodies on muscle specimens, which revealed mutations in the NEB gene. Method We pathologically assessed seven cases from three families, who presented with AMC/FADS. Targeted genetic analysis for Ashkenazi Jewish mutation (in relevant patients) was followed by next‐generation sequencing and multiplex ligation‐dependent probe amplification. Results All cases were detected on prenatal ultrasound. Characteristic nemaline bodies on muscle specimens were demonstrated in at least one case in each of the nuclear families. In the Ashkenazi Jewish family, the known founder mutation was compounded by one recurrent novel splice site. The other two families were of Chinese and Korean origins, and only one pathogenic heterozygous mutation was detected in each. Conclusions Nemaline myopathy due to NEB mutation(s) leads to FADS/AMC. Currently, mutated NEB is under‐recognized as a cause for AMC/FADS. Our study attempts to raise recognition of this gene as a cause, suggesting the NEB gene should be included in genetic panels used for FADS/AMC cases and be fully covered when EXOME sequencing is utilized. A heterozygous mutation may suggest either compounding undetected one or digenic interaction that requires further genetic analyses. © 2016 John Wiley & Sons, Ltd. WHAT'S ALREADY KNOWN ABOUT THIS TOPIC? NEB gene mutations account mainly for mild congenital nemaline myopathy and are under‐recognized as a cause of FADS/AMC. WHAT DOES THIS STUDY ADD? NEB gene mutations should be sought not only when mild nemaline myopathy is present, but also in fetal akinesia deformation sequence/arthrogryposis multiplex congenita cases. As characteristic nemaline bodies might not appear prenatally in muscle biopsies, genetic testing is favorable. Therefore, the NEB gene should be included in mutations panels or should fully be covered when EXOME sequencing is performed.