Paternal mosaicism of an STXBP1 mutation in OS

Abstract

Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.

Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers

“…STXBP1 mutations were first reported in five Japanese patients with Ohtahara syndrome (Saitsu et al., ). Since then, multiple studies have expanded the clinical spectrum of STXBP1 encephalopathy showing that it accounts for about 22% of cases with nonlesional Ohtahara syndrome, 6% of nonsyndromic early onset EE, and 2% of West syndrome of unknown etiology (Saitsu et al., , ,b; Deprez et al., ; Mignot et al., ; Milh et al., ; Otsuka et al., ). Epilepsy onset is within the first 4 months of age, although later onset has been reported for rare cases (Hamdan et al., ; Mignot et al., ).…”

Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A

“…8,13,14,21 In addition, there is increasing awareness that STXBP1 mutations may also cause IS as the presenting epileptic feature, broadening the recognized clinical phenotypic consequences of genetic variation at the STXBP1 locus. 10,12,16 In one of the same studies implicating a link between STXBP1 and IS, five of the six subjects harboring STXBP1 mutations manifested nonspecific epileptic phenotypes.…”

Emerging role of the KCNT1 Slack channel in intellectual disability

“…To date, alterations in five different genes have been found in patients: ion channels KCNQ2 (Kv7.2; Saitsu et al, 2012a; Kato et al, 2013), SCN2A (Nav1.2; Nakamura et al, 2013; Touma et al, 2013), and KCNT1 (Slack; Martin et al, 2014); the transcription factor ARX (Kato et al, 2007; Absoud et al, 2010; Giordano et al, 2010; Fullston et al, 2010; Eksioglu et al, 2011); and the synaptic binding protein STXBP1 (Saitsu et al, 2008, 2010, 2011; Mignot et al, 2011; Milh et al, 2011). Interestingly, mutations in SCN2A and KCNT1 have also been found in patients diagnosed with MMPSI.…”