A patient with PLACK syndrome with a novel splicing mutation in CAST: the evidence for a loss-of-function mechanism through mis-splicing

Here we report a case of a patient with PLACK syndrome born in an isolated population with multiple consanguineous marriages. Whole exome sequencing and subsequent Sanger sequencing verified the splice variant c.1209+2T>G in the CAST gene. The mutation described in this paper is a very rare example of a splice-site mutation that, in addition to damaging the normal splice site, creates a new splice site and changes the open-reading frame at the mRNA level. Our analysis has confirmed a loss-of-function mechanism via mRNA nonsense-mediated decay as are result of this mutation. PLACK syndrome is a relatively recently defined generalized peeling skin syndrome that has been reported with major skin manifestations and sometimes atypical features. We report the case of a 5-year-old boy with PLACK manifestations. Whole exome sequencing and subsequent Sanger sequencing identified a putative splice variant c.1209+2T>G in CAST (NM_001042440.5). Moreover, mRNA sequencing confirmed the abnormal alternative splicing of the CAST gene, leading to the addition of one nucleotide to the correct open-reading frame at the mRNA level. Segregation and expression analysis revealed that this loss-of-function via mRNA nonsense-mediated decay could be the causative pathogenic mechanism responsible for this patient's phenotype. This study extends our understanding of the various phenotypic and genotypic features of PLACK syndrome.