Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.
Bottom Line: We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome diagnosis) and neurodevelopmental delay associated with compound heterozygous mutations in PLCB1.In order to investigate the presence of a second PLCB1 mutation, direct Sanger sequencing of the coding region and flanking intronic regions was undertaken, revealing a novel heterozygous intron 1 splice site variant (c.99+1G>A) in both the index individual and the father.PLCB1-EIEE is now reported in a number of different EIEE phenotypes and our report provides further evidence for phenotypic pleiotropy encountered in early infantile epilepsy syndromes.
Affiliation: Neurosciences Unit, Developmental Neurosciences, University College London, Institute of Child Health, London, UK; Department of Neurology, Great Ormond Street Hospital, London, UK.Show MeSH
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Mentions: A routine diagnostic microarray study identified a heterozygous 476kb deletion on chromosome 20p12.3 from base pairs (bp) 8 099 252 to 8 575 333 (Human Genome Build 37; Fig.1). This deleted region, from rs6140539 to rs6118262, encompassed part of the 5′ region and the first three coding exons of PLCB1. Microarray studies of parental DNA confirmed the same heterozygous deletion in the mother of the proband and absence of the deletion in the father. The telomeric and centromeric genomic breakpoints were further characterized and mapped to 8 094 442 to 8 094 510 bp and 8 580 654 to 8 580 722 bp respectively (Fig.2). Further analysis revealed that the telomeric and centromeric breakpoints lie within two L1 family long interspersed nuclear elements (LINEs), LIPA3 and LIPA2, occurring at chromosome 20, 8 089 514 to 8 095 564 bp, and chromosome 20, 8 575 749 to 8 581 774 bp. In order to determine whether the proband harboured a second PLCB1 mutation on the paternally derived allele, direct Sanger sequencing was performed of the whole coding sequence of PLCB1 (including flanking exon–intron boundaries) for the child and both parents. This revealed a splice site variant in intron 1 (c.99+1G>A) in both the index individual and in the father (Fig.2). This splice site mutation, affecting the first base after exon 1, was predicted to cause deleterious splicing (Berkeley Drosophila Genome project: www.fruitfly.org/seq_tools/splice.html), thereby either leading to nonsense-mediated decay or a truncated protein product.
Affiliation: Neurosciences Unit, Developmental Neurosciences, University College London, Institute of Child Health, London, UK; Department of Neurology, Great Ormond Street Hospital, London, UK.