NSF gene variants cause developmental and epileptic encephalopathy 96: expanding genotype and phenotypic spectrum...

Developmental and epileptic encephalopathy 96 (DEE96, OMIM 619340) is a rare autosomal dominant disorder caused by heterozygous variants in the NSF gene, encoding a key AAA + ATPase involved in SNARE-mediated membrane fusion. To date, only four pathogenic variants have been reported.

Trio whole-exome-sequencing and Sanger validation were performed in a fetus presenting with multiple prenatal anomalies. Bioinformatic analyses and literature review were conducted to characterize genotype-phenotype correlations.

We identified a novel de novo heterozygous missense variant [c.1055 A>G; p (Asn352Ser)] in the D1 domain of NSF, classified as likely pathogenic per ACMG/AMP criteria. Prenatal ultrasound revealed increased nuchal fold thickness, left clubfoot, severe anemia with cardiac enlargement, and hepatosplenomegaly. Increased nuchal fold thickness and left clubfoot had not been previously documented in DEE96 cases. This represents the second prenatal diagnosis and fifth case overall.

Our findings expand the genotypic and phenotypic spectrum of DEE96, demonstrating that DEE96 manifests as a multisystem disorder with prenatal onset. The high incidence of severe anemia suggests hematological involvement may be a characteristic feature. These observations support considering NSF variants in the differential diagnosis of complex fetal syndromes with neurological and hematological abnormalities.