Novel NEXMIF gene pathogenic variant in a female patient with refractory epilepsy and intellectual disability

Abstract

We identified a novel nonsense de novo pathogenic variant of the NEXMIF gene in a 29 year-old female patient with refractory epilepsy and mild intellectual disability. The patient presented with episodic atypical absence status (AS), the longest duration of her seizures was approximately 36 hr. She also had occasional eyelid myoclonia during absence seizure. EEG highlighted a photosensitivity phenomenon and generalized epileptiform discharges that were induced by eye closure. Whole exome sequencing revealed a novel nonsense pathogenic variant c.1063delC (p.L355*) in exon 3 of the NEXMIF gene. The mRNA expression of NEXMIF in this female patient was below −2 SD from the mean of control group. In addition to adding a novel pathogenic variant type to the NEXMIF variant database and conducting mRNA studies, this report also describes a unique phenotype in a patient with atypical AS associated with a NEXMIF variant. We discuss implications for medication management in similar patients.

Candidate Genes for Eyelid Myoclonia with Absences, Review of the Literature

“…Finally, two more female patients with alterations in the NEXMIF gene and a phenotype resembling EMA have been reported. Wu et al (2020) described a woman with refractory epilepsy and EEG features similar to those described in EMA who was a carrier of a nonsense variant in NEXMIF (p.Leu355*) ( Table 2 ) [ 43 ]. Samanta and Willis (2020) identified a frameshift mutation (p.Asp573Serfs*11) in a girl with intractable seizures diagnosed with EMA [ 2 ].…”

Next-Generation Sequencing Technologies and Neurogenetic Diseases

“…Using NGS, Ittiwut et al [88] identified a de novo variant (c.467A>T) in ATP6V0C in a patient with intractable epilepsy and intellectual disability, which was a conserved termination codon mutation. Meanwhile, Wu et al suggested that NEXMIF with X-inactivation patterns might have contributed to the mild intellectual disability [89].…”

Heterozygous Nexmif female mice demonstrate mosaic NEXMIF expression, autism-like behaviors, and abnormalities in dendritic arborization and synaptogenesis

“…The reported individuals with NEXMIF -dependent ASD show impaired communication, repetitive behaviors, seizures, ID, and microcephaly. Interestingly, although only male cases were reported in earlier studies, recent clinical reports indicate that autistic characteristics are also observed in females with NEXMIF mutations [ [17] , [18] , [19] , [20] , [21] , [22] , [23] ]. Due to infertility of affected males, females with inherited NEXMIF mutations are heterozygous and therefore haploinsufficient in NEXMIF.…”