Axonal polyneuropathy and intellectual disability caused by biallelic NEMF variants identified by reviewing the previously acquired whole exome sequencing data: A case report

Biallelic loss-of-function variants in the nuclear export mediator factor ( NEMF ) gene are associated with a rare autosomal recessive neuropathy characterized by motor-predominant axonal polyneuropathy and variable intellectual disability. Since its first report in 2017, most cases have been described in individuals of Middle Eastern origin. We describe a Japanese boy with infantile-onset chronic motor axonal polyneuropathy and mild intellectual delay. Muscle weakness gradually progressed from distal to proximal muscles. Intravenous immunoglobulin (IVIG) therapy resulted in only partial and temporary improvement. By age five, he became non-ambulatory and required intermittent ventilatory support. Whole-exome sequencing (WES) performed in 2016 failed to identify a genetic diagnosis. However, reanalysis of the same WES data in 2022 revealed two biallelic pathogenic splice-site variants in the NEMF gene—c.945+1delG (maternal) and c.2929-2A>G (paternal)—both predicted to cause aberrant splicing and premature translation termination. RNA analysis confirmed these findings. Public transcriptomic data from NEMF -knockdown cells revealed upregulation of immune-related gene sets, potentially explaining the transient response to IVIG. This is the first reported case of NEMF -related neuropathy in East Asia. Our findings suggest that immune dysregulation may contribute to the disease mechanism in some cases. Furthermore, this case illustrates that in some rare diseases, reviewing previous next-generation sequencing (NGS) data that initially yielded no significant findings may lead to diagnostic success, thanks to the rapidly expanding body of knowledge on genotype–phenotype correlations. Periodic reinterpretation of genomic data can therefore be a valuable strategy in undiagnosed rare conditions.