Pathogenic variants in in the CSTB gene, which encodes cystitin B, are associated with the autosomal recessive disorder Unverricht-Lundborg disease (ULD), or progressive myoclonic epilepsy type 1. Most patients with ULD are homozygous for an expanded dodecamer repeat in the promotor region of the gene. Compound heterozygotes who have the dodecamer repeat on one allele and a point pathogenic variant (usually loss-of-function) on the other typically exhibit a more severe phenotype. It was previously thought that harboring two loss of function variants in the CSTB gene was incompatible with life. However, four patients with homozygous loss of function CSTB variants from two unrelated families were recently described.  These patients exhibit a severe and unique phenotype characterized by microcephaly, profound developmental delay, early onset epilepsy, and dyskinetic movements of variable severity.

We utilized whole exome sequencing (WES) to investigate the underlying genetic cause of microcephaly, global developmental delay, hypotonia, hyperkinetic movement disorder, and epilepsy in a 23 month old Caucasian female. We compare the phenotype and genotype in the proband with previously reported patients. 

WES revealed the likely pathogenic variants c.67-1G>C (IVS1-1G>C) and c.202C>T (p.R68*) in the CSTB gene. We report the fifth patient, to our knowledge, to harbor biallelic loss of function variants in the CSTB gene. While our patient is phenotypically similar to the previously described patients, she developed a more severe drug-refractory epilepsy.

Our data expand the phenotypic and genotypic spectra of CSTB-related disorders and provide additional evidence that biallelic loss of function variants in CSTB cause a unique phenotype characterized by microcephaly and profound developmental delay with or without early onset dyskinetic movements and epilepsy. Additional functional studies are needed to investigate the molecular basis of the allelic heterogeneity in the CSTB gene.