A De Novo Splicing Mutation of STXBP1 in Epileptic Encephalopathy Associated with Hypomyelinating Leukodystrophy

Deleterious variations in <i>STXBP1</i> 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 <i>STXBP1</i> encephalopathy (<i>STXBP1</i>-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. A girl was first diagnosed with unexplained disorders of movement and cognition, which later developed into <i>STXBP1</i>-E with unexpected leukoaraiosis and late onset of seizures. Genetic screening and molecular tests alongside neurological examinations were employed to investigate the genetic etiology and establish the diagnosis. A heterozygous mutation of c.37+2dupT at the <i>STXBP1</i> splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) did not result in any truncated proteins but immediately triggered mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of <i>STXBP1</i>. The patient showed atypical phenotypes characterized by hypomyelinating leukodystrophy, and late onset of epileptic seizures, which had never previously been delineated in <i>STXBP1</i>-E. These findings strongly indicated that the haploinsufficiency of <i>STXBP1</i> could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies.