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Title: PCDH19 Pathogenic Variants in Males: Expanding the Phenotypic Spectrum.
Austin Authors: Kolc, Kristy L;Møller, Rikke S;Sadleir, Lynette G;Scheffer, Ingrid E ;Kumar, Raman;Gecz, Jozef
Affiliation: Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Melbourne, VIC, Australia
Adelaide Medical School, the University of Adelaide, Adelaide, SA, Australia
Epilepsy Research Centre
Department for Regional Health Research, University of Southern Denmark, Odense, Denmark
Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre, Dianalund, Denmark
Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia
Healthy Mothers and Babies, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
The Florey and Murdoch Institutes, Melbourne, VIC, Australia
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Issue Date: 28-Aug-2020
Date: 2020
Publication information: Advances in Experimental Medicine and Biology 2020; 1298: 177-187
Abstract: 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.
DOI: 10.1007/5584_2020_574
Journal: Advances in Experimental Medicine and Biology
PubMed URL: 32852734
ISSN: 0065-2598
Type: Journal Article
Subjects: Epilepsy
Pathogenic variant
Appears in Collections:Journal articles

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