The Neurite EXtension and MIgration Factor (NEXMIF), previously called KIAA2022, is an X-linked gene that plays an important role in early brain development. The underlying molecular mechanism causing NEXMIF-E is likely loss-of-function, since all known pathogenic variants are truncating variants (stop gain, frameshift) or larger structural variants. Neither missense nor splice site variants have been established as pathogenic to date.
There are a few recurrent pathogenic variants, however; most variants have only been seen once. Somatic mosaicism in patients and presumed gonadal mosaicism in parents has been reported.
To date no clear genotype–phenotype correlations have emerged, which is not unexpected since reported pathogenic variants are protein truncating variants or deletions; all expected to lead to haploinsufficiency. The only clear genotype-phenotype correlation is related to sex correlating with the X-chromosome location of the gene. Overall males generally have more severe developmental impairment and females have epilepsy more frequently, but the clinical picture varies from unaffected to severely affected.
Functional analyses are not available for NEXMIF-variants at present.
Most patients are diagnosed though next-generation sequencing methods such as gene panels or whole-exome/genome sequencing. Larger structural variants can only be discovered through microarray analysis or genome sequencing.
NEXMIF