PCDH19 Pathogenic Variants in Males: Expanding the Phenotypic Spectrum

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Protocadherin-19 (PCDH19) pathogenic variants cause an infantile epilepsy syndrome, predominantly in females, termed Girls Clustering Epilepsy.
• Debate exists regarding affected males, with rare cases of postzygotic somatic mosaic variants showing similar clinical features to females, while germline variants are considered asymptomatic.
• No standardized neuropsychiatric assessment has been performed on males with PCDH19 pathogenic variants.

Purpose of the Study:

• To conduct a standardized neuropsychiatric assessment of males with PCDH19 pathogenic variants.
• To investigate the phenotypic spectrum of PCDH19 variants in males.
• To propose a revised terminology for PCDH19-related epilepsy.

Main Methods:

• Studied 15 males (aged 2-70 years) with PCDH19 pathogenic variants (9 mosaic, 6 transmitting).
• Families completed standardized clinical assessments: Social Responsiveness Scale, Strengths and Difficulties Questionnaire, Behavior Rating Inventory of Executive Function, and Dimensional Obsessive-Compulsive Scale.
• Confirmed mosaicism in blood and skin fibroblasts where applicable.

Main Results:

• Identified neuropsychiatric abnormalities in two males with germline PCDH19 possibly pathogenic variants; one had a history of severe encephalopathy.
• Described a non-penetrant somatic mosaic male with mosaicism confirmed in blood but not skin fibroblasts.
• Transmitting hemizygous males were generally unaffected, unlike males with postzygotic somatic mosaic variants who exhibited a similar neuropsychiatric profile to mosaic females.
• Estimated penetrance for mosaic PCDH19 pathogenic variants in males at 85%.

Conclusions:

• Transmitting males with PCDH19 variants are typically asymptomatic.
• Males with postzygotic somatic mosaic PCDH19 variants display a similar neuropsychiatric profile to mosaic females due to X-chromosome inactivation.
• Proposed the new term Clustering Epilepsy (CE) to encompass affected males and females presenting with infantile onset of seizure clusters.