X-chromosome inactivation and PCDH19-associated epileptic encephalopathy: A novel PCDH19 variant in a Chinese family.

Background: Developmental and epileptic encephalopathy 9 (DEE9, MIM #300088) is an early onset seizure disorder associated with cognitive impairment and behavioral disturbances. It is caused by mutation in protocadherin 19 with an unusual X-linked inheritance selectively involving heterozygous females or mosaic hemizygous males, while hemizygous males are unaffected. Cellular interference was the postulated mechanism underlying the unusual inheritance pattern.

Case Report: We report a Chinese girl who presented with severe treatment refractory seizures at 26 months of age and was found heterozygous for a novel likely pathogenic missense variant NM_001184880.2:c.488T>A p.(Val163Glu) in PCDH19. Her younger sister, who was also heterozygous for the variant, was asymptomatic with normal development at the time of reporting at 37 months of age. X-chromosome inactivation study by androgen receptor gene methylation assay in DNA from peripheral leukocytes was performed which demonstrated somewhat skewed X-chromosome inactivation in the proband and extremely skewed X-chromosome inactivation in the asymptomatic younger sibling.

Conclusion: PCDH19-related seizure disorder has incomplete penetrance and variable expressivity. Further studies are required to determine the potential role of X-chromosome inactivation on the phenotypic variability and patient outcomes. Liberal referral for PCDH19 testing among female patients with early-onset seizures should be considered to enhance case detection.