PCDH19 pathogenic variants in males: Expanding the phenotypic spectrum

Kristy L. Kolc, Rikke S. Møller, Lynette G. Sadleir, Ingrid E. Scheffer, Raman Kumar, Jozef Gecz*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingBook chapterResearchpeer-review


Protocadherin-19 (PCDH19) pathogenic variants cause an infantile onset epilepsy syndrome called Girls Clustering Epilepsy due to the vast majority of affected individuals being female. This syndromic name was developed to foster early recognition and diagnosis in infancy. It has, however, sparked debate, as, there are rare males with postzygotic somatic, and therefore, mosaic, PCDH19 pathogenic variants with similar clinical features to females. Conversely, “transmitting” males with germline inherited PCDH19 variants are considered asymptomatic. To date, there has been no standardized neuropsychiatric assessment of males with PCDH19 pathogenic variants. Here, we studied 15 males with PCDH19 pathogenic variants (nine mosaic and six transmitting) aged 2 to 70 years. Our families completed a survey including standardized clinical assessments: Social Responsiveness Scale, Strengths and Difficulties Questionnaire, Behavior Rating Inventory of Executive Function, and Dimensional Obsessive-Compulsive Scale. We identified neuropsychiatric abnormalities in two males with germline PCDH19 possibly pathogenic variants. One had a prior history of a severe encephalopathic illness, which may have been unrelated. We also describe a non-penetrant somatic mosaic male with mosaicism confirmed in blood, but not identified in skin fibroblasts. Our data suggest that transmitting hemizygous males are generally unaffected, in contrast to males with postzygotic somatic mosaic variants who show a similar neuropsychiatric profile to females who are naturally mosaic, due to X-chromosome inactivation. The penetrance of PCDH19 pathogenic variants has been estimated to be 80%. Like females, not all mosaic males are affected. From our small sample, we estimate that males with mosaic PCHD19 pathogenic variants have a penetrance of 85%. With these insights into the male phenotypic spectrum of PCDH19 epilepsy, we propose the new term Clustering Epilepsy (CE). Both affected females and males typically present with infantile onset of clusters of seizures.

Original languageEnglish
Title of host publicationCell Biology and Translational Medicine, Volume 10 : Stem Cells in Tissue Regeneration
EditorsKursad Turksen
Publication date2020
ISBN (Print)978-3-030-60011-2
ISBN (Electronic)978-3-030-60012-9
Publication statusPublished - 2020
SeriesAdvances in Experimental Medicine and Biology


  • Epilepsy
  • Mosaic
  • Neuropsychiatric
  • Pathogenic variant
  • PCDH19
  • Humans
  • Middle Aged
  • Child, Preschool
  • Male
  • Penetrance
  • Young Adult
  • Cadherins/genetics
  • Epilepsy/genetics
  • Adolescent
  • Adult
  • Female
  • Mosaicism
  • Aged
  • Mutation
  • Child


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