Abstracts

Rationale: Mutations in the PCDH19 gene (OMIM: 300460) are associated with early infantile epileptic encephalopathy type 9 (OMIM: 300088) which is also referred to as epilepsy and intellectual disability restricted to females. The PCDH19 gene is located on chromosome Xq22.1 and encodes protocadherin-19 protein which is part of a subclass of protocadherins belonging to the cadherin superfamily. Although recent advancements in molecular sequencing technology have provided patients with the opportunity to pursue genetic testing for PCDH19-suspicious clinical presentations, benefits and limitations of these testing options remain complex for clinicians and patients to navigate on an ongoing basis. Methods: Here we present the benefits and limitations of chromosomal microarray (array-CGH), single-gene sequence analysis, gene-panel testing, and whole exome sequencing as clinical tools available for the identification of clinically significant PCDH19 mutations. Although each test has a role in the diagnosis of PCDH19-associated disorders, there are limitations of each test about which patients and clinicians should know for counseling purposes. Results: Of the 114 PCDH19 mutations described to date in the Human Gene Mutation Database (HGMD), 71 (62%) are missense/nonsense mutations, 3 (~3%) are splicing mutations, 12 (~10%) are small deletions, 17 (15%) are small insertions, 3 (~3%) are small indels, and 8 (7%) are gross deletions; thus, test selection can be critical. Conclusions: Here we provide a retrospective evaluation of the specific diagnosis associated with these 114 reported PCDH19 mutations in HGMD, and provide an assessment of what would have been the most appropriate clinical tests selection to have diagnosed each individual case in an optimal and efficient manner.