Abstracts

Rationale: Neurite extension and migration factor (NEXMIF), previously called KIAA2022, is an X-linked gene, which is thought to play an important role in early brain development. Loss-of-function mutations in NEXMIF are associated with intellectual disability (ID), autism spectrum disorder (ASD) and epilepsy, including developmental and epileptic encephalopathies (DEEs), with females being less severely affected than males. We describe the phenotypic spectrum of NEXMIF encephalopathy in 14 patients from 8 families with pathogenic or possibly pathogenic (1 family) NEXMIF variants. Methods: Patients were referred to the Epilepsy Research Center by collaborating physicians. They were phenotyped using a validated epilepsy questionnaire, together with a developmental history and review of EEG and MRI data. NEXMIF variants were identified by gene panel screening or exome sequencing. Results: We identified 5 apparently de novo truncating NEXMIF pathogenic variants in 2 males and 4 females, including a recurrent p.Arg322* mutation in 2 sisters. This familial mutation suggests parental mosaicism, which we could not detect despite deep sequencing. We also identified a somatic mosaic p.Ser882* nonsense variant in a male patient. Mean age of seizure onset in this group was 22 months (15 mth-3 yr). Absence seizures (including myoclonic absences and absences with eyelid myoclonia) and refractory myoclonic seizures (including myoclonic status epilepticus) were prominent. All patients had moderate to profound ID. Other recurrent features included dysmorphic features, behavioural problems and ASD. We also identified 7 subjects from 2 families with X-linked segregation of NEXMIF variants. One family comprised 4 affected females with p.Arg481* nonsense mutation. All affected females had ID or developmental delay, however, only one had refractory epilepsy. A NEXMIF missense variant (p.Asp519Val) was identified in a second family in a mother and her two sons with ID. This variant was interpreted as possibly pathogenic based on its absence from ExAC and gnomAD and predicted deleterious effect with in silico prediction tools. Interestingly, this family had a milder epilepsy phenotype with onset of absences and generalised tonic-clonic seizures in late childhood or adolescence.  Conclusions: The epilepsy spectrum associated with NEXMIF encephalopathy is broad, ranging from severe generalised DEEs to milder generalised epilepsies with cognitive impairment. This is the first report of mother to daughter transmission and somatic mosaicism for NEXMIF encephalopathy. We suggest a rare NEXMIF missense variant might be disease-causing, though further functional testing is necessary to claim a pathogenic role. Funding: Not applicable