Epilepsy: Unverricht-Lundborg Disease via the CSTB Gene

Unverricht-Lundborg disease, also known as progressive myoclonic epilepsy 1A, and Myoclonic epilepsy of Unverricht and Lundborg, is a rare hereditary neurodegenerative disorder characterized by onset of neurodegeneration between 6 and 13 years of age and generalized myoclonic seizures. Onset peaks at around age 12-13. Other neurological manifestations such as ataxia are rare. Cognitive impairment varies from absent to moderate. Treatment is available (Crespel et al. 2016. PubMed ID: 27582036).

Unverricht-Lundborg disease is inherited in an autosomal recessive manner and is caused by pathogenic variants in CSTB, which encodes cystatin B, a member of the superfamily of cysteine protease inhibitors.

CSTB pathogenic variants include missense, nonsense, splicing, small frameshift deletions and small indels (Human Gene Mutation Database). The most common pathogenic variant is an unstable expansion of a 12-nucleotide (dodecamer) repeat 5'-CCC-CGC-CCC-GCG-3' in the promoter region. This expansion accounts for approximately 90% of the patients worldwide and 99% of the cases in Finland, most of them in a homozygous state (Hyppönen et al. 2015. PubMed ID: 25770194; Crespel et al. 2016. PubMed ID: 27582036). Large deletions and duplications involving CSTB have not been reported.

Sequencing will not identify the most common dodecamer repeat expansion in the CSTB gene (90% of cases). Therefore, the sensitivity of this test is expected to be low (10% of cases).

To date, no large deletions/duplications have been reported involving CSTB.

This test provides full coverage of all coding exons of the CSTB gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.