PCDH19 Pathogenic Variants in Males: Expanding the Phenotypic Spectrum
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 diag
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PCDH19 Pathogenic Variants in Males: Expanding the Phenotypic Spectrum Kristy L. Kolc, Rikke S. Møller, Lynette G. Sadleir, Ingrid E. Scheffer, Raman Kumar, and Jozef Gecz Abstract Electronic Supplementary Material: The online version of this chapter (https://doi.org/10.1007/5584_2020_574) contains supplementary material, which is available to authorized users. K. L. Kolc and R. Kumar Adelaide Medical School, the University of Adelaide, Adelaide, SA, Australia Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia R. S. Møller Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre, Dianalund, Denmark Department for Regional Health Research, University of Southern Denmark, Odense, Denmark L. G. Sadleir Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand I. E. Scheffer Department of Medicine, Epilepsy Research Centre, The University of Melbourne, Austin Health, Melbourne, VIC, Australia Department of Paediatrics, Royal Children’s Hospital, The University of Melbourne, Melbourne, VIC, Australia The Florey and Murdoch Institutes, Melbourne, VIC, Australia J. Gecz (*) Adelaide Medical School, the University of Adelaide, Adelaide, SA, Australia Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia Healthy Mothers and Babies, South Australian Health and Medical Research Institute, Adelaide, SA, Australia e-mail: [email protected]
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
K. L. Kolc et al.
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-chro
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