A novel de novo splicing mutation of STXBP1 in epileptic encephalopathy associated with hypomyelinating leukodystrophy

Background: Deleterious variations in STXBP1 are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as STXBP1 encephalopathy (STXBP1-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. The girl first diagnosed with the unexplained disorders of movement and cognitive later was developed into STXBP1-E with unexpected leukoaraiosis and late-onset of seizures. Methods: : The genetic screening and molecular tricks including trio Whole Exome Sequencing (WES), Sanger sequencing, bioengineering with CRISPR/Cas9, Western blot, qPCR/RT-PCR and bioinformatic analyses alongside neurological examinations were employed to investigate the genetic etiology and established the diagnosis. Results: : A novel de novo heterozygous mutation of c.37+2dupT at STXBP1 splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) didn't result in any truncated proteins, but immediately trigger mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of STXBP1. The patient showed the atypical phenotypes characterized by hypomyelinating leukodystrophy and late-onset of epileptic seizures, which had never previously been delineated in STXBP1-E. Conclusion: The findings strongly implicated that the haploinsufficiency of STXBP1 could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies.