A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy

Seizure. 2019 Oct;71:161-165. doi: 10.1016/j.seizure.2019.07.019. Epub 2019 Jul 25.


Purpose: We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy genes.

Methods: Whole-exome sequencing was performed for the 2 siblings and their unaffected parents, in addition to fibroblast cell culture, RNA extraction and reverse-transcription, and cDNA PCR. Brain tissue from one of the siblings was collected post-mortem for neuropathological examination, including histology and immunohistochemistry.

Results: Ade novo nucleotide change (c.566 T > A; p.(Met189Lys)) in exon 4 of the BSCL2 gene was detected in the 2 siblings, and confirmed by Sanger sequencing. This variant was absent in the parents and in a third, unaffected sibling.

Conclusion: Given thede novo nature of the variant, its absence from public and in-house databases, our in silico pathogenicity predictions, and co-segregation of the variant with the disease phenotype, we believe that this novel variant is associated with the epileptic encephalopathy phenotype of the 2 siblings. Our findings provide the first evidence of an association between a heterozygous BSCL2 variant and developmental and early infantile epileptic encephalopathy. Further functional studies will be needed to elucidate the pathophysiological mechanisms underlying this new BSCL2-associated phenotype.

Keywords: BSCL2; Early infantile epileptic encephalopathy; Seipin; Whole exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Child
  • Drug Resistant Epilepsy / diagnosis*
  • Drug Resistant Epilepsy / genetics
  • Drug Resistant Epilepsy / physiopathology
  • Exome Sequencing
  • Fatal Outcome
  • Female
  • GTP-Binding Protein gamma Subunits / genetics*
  • Humans
  • Infant
  • Male
  • Mutation, Missense
  • Neurodevelopmental Disorders / diagnosis
  • Neurodevelopmental Disorders / genetics
  • Neurodevelopmental Disorders / physiopathology
  • Pedigree
  • Siblings
  • Spasms, Infantile / diagnosis*
  • Spasms, Infantile / genetics
  • Spasms, Infantile / physiopathology


  • BSCL2 protein, human
  • GTP-Binding Protein gamma Subunits