Abstracts

Rationale: Phospholipase C beta 1 (PLCB1) is a post-synaptic receptor-activated G protein-coupled phosphodiesterase, which plays a key role in diverse developmental and functional aspects of the central nervous system. Homozygous deletions of chromosome 20p13 disrupting the promoter region and first 3 coding exons of PLCB1 have been described in two reports of early infantile epileptic encephalopathy (EIEE) occurring within consanguineous families (1,2). We describe a patient presenting with developmental delay and epilepsy with novel PLCB1 mutations. Methods: Case note review and molecular genetic investigations. Results: The patient presented at 6 months of age with developmental regression followed by the onset of intractable focal and generalised seizures from 10 months. EEG revealed generalised slowing and multi-focal discharges. MRI brain showed a hypoplastic corpus callosum and generalised decrease in brain volume. Diagnostic microarray studies revealed a heterozygous 476Kb deletion of 20p13 (encompassing part of PLCB1), which was maternally inherited. The deletion breakpoints were between 8,094,442-8,094,510 bp and 8,580,65-8,580,722 bp. Direct Sanger sequencing revealed a novel intron 1 splice site variant, which was paternally inherited (c.99+1G>A). Conclusions: Mutations in PLCB1 cause a wide spectrum of early onset epileptic encephalopathies, now including non-specific EIEE. The heterozygous deletion identified in this African-American case appears almost identical to that reported in a family of Palestinian descent suggesting a role for the flanking LINE elements in this recurrent deletion (2). This novel report of compound heterozygosity expands the PLCB1 phenotype and genotype and provides an excellent example of chromosomal microdeletions unravelling deleterious recessive mutations which cause human disease. References: 1. Kurian MA, Meyer E, Vassallo G et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain 2010;133:2964-70. 2. Poduri A, Chopra S, Neilan E et al. Homozygous PLCB1 Deletion Associated with Malignant Migrating Partial Seizures in Infancy. Epilepsia 2012; 53:e146-e150.