Identification of four novel PCDH19 Mutations and prediction of their functional impact.

The PCDH19 gene encodes protocadherin-19, a transmembrane protein with six cadherin (EC) domains, containing adhesive interfaces likely to be involved in neuronal connection. Over a hundred mostly private mutations have been identified in girls with epilepsy, with or without intellectual disability (ID). Furthermore, transmitting hemizygous males are devoid of seizures or ID, making it difficult to establish the pathogenic nature of newly identified variants. Here, we describe an integrated approach to evaluate the pathogenicity of four novel PCDH19 mutations. Segregation analysis has been complemented with an in silico analysis of mutation effects at the protein level. Using sequence information, we compared different computational prediction methods. We used homology modeling to build structural models of two PCDH19 EC-domains, and compared wild-type and mutant models to identify differences in residue interactions or biochemical properties of the model surfaces. Our analysis suggests different molecular effects of the novel mutations in exerting their pathogenic role. Two of them interfere with or alter functional residues predicted to mediate ligand or protein binding, one alters the EC-domain folding stability; the frame-shift mutation produces a truncated protein lacking the intracellular domain. Interestingly, the girl carrying the putative loss of function mutation presents the most severe phenotype.

PCDH19-related epilepsy and Dravet Syndrome: Face-off between two early-onset epilepsies with fever sensitivity.

Aim of this study is to compare PCDH19-related epilepsy and Dravet Syndrome (DS) in order to find out differences between these two infantile epilepsies with fever sensitivity. We retrospectively reviewed the medical records of 15 patients with PCDH19-related epilepsy and 19 with DS. Comparisons were performed with Fisher's exact test or Student's t-test. Females prevailed in PCDH19-related epilepsy. Epilepsy onset was earlier in DS (5.0+2.1 vs 11.2+7.0months; p<0.05). The second seizure/cluster occurred after a longer latency in PCDH19-related epilepsy rather than in DS (10.1±13.6 vs 2.2±2.1months; p<0.05). Seizures were mainly single and prolonged seizures in DS, and brief and clustered in PCDH19-related epilepsy. Myoclonic and clonic seizures have been found only in DS. Other types of seizures were found in both epilepsies with a prevalence of GTCS and atypical absences in DS, and focal motor and hypomotor seizures in PCDH19-related epilepsy. Seizures with affective symptoms have been confirmed to be typical of PCDH19-related epilepsy. Status Epilepticus equally occurred in both groups. Photosensitivity was detected only in DS. No differences were found about the presence of intellectual disabilities and behavioral disturbances. We were able to find out some distinctive features, which could address the diagnosis towards DS or PCDH19-related epilepsy, since first manifestation. These considerations suggest to definitively considering PCDH19 gene as cause of a proper epileptic phenotype.