The PCDH19 gene is an important gene contributing to brain function. Genetic changes (called pathogenic variants or mutations) in the PCDH19 gene cause disease. This predominantly occurs in girls and the characteristic feature of this disease is seizures occurring in clusters, hence the name PCDH19 Clustering Epilepsy (CE). Some girls (20%) with a PCDH19 pathogenic variant have no clinical features. Affected females with pathogenic variants vary in the severity of their illness, ranging from mild epilepsy, to mild epilepsy with learning difficulties to a severe treatment-resistant epilepsy accompanied by intellectual disability and mental health disorders, such as autism spectrum disorder and behavioural problems. How much this condition affects an individual varies significantly, even amongst individuals in the same family with the same pathogenic variant.
The first symptoms are usually epileptic seizures that often begin in the first year of life, but may begin up to 3 years of age. The seizures come in clusters, that is, many seizures occur over several days followed by periods of time (up to months) without seizures. Girls may have slow development and behavioural problems, and sometimes lose their skills. The more severely affected will develop an intellectual disability, ranging from mild to profound. Individuals with CE are otherwise healthy, with normal functioning of the rest of their bodies.
The PCDH19 gene lies on the X-chromosome, which is one of the sex chromosomes. Males have a single X-chromosome and a Y chromosome, while females have two X chromosomes. CE can be passed down (inherited) within a family or found in an individual with no family history of the disorder. Females with a pathogenic variant have a high likelihood of being affected, but males with the pathogenic variant typically do not have seizures and have normal intelligence.
Only a small number of males have been reported who are affected by PCDH19 pathogenic variants. This is due to a situation called ‘somatic mosaicism’, where the affected males have a mixture of normal and abnormal copies of the PCDH19 gene in their brains.
Pathogenic variants in PCDH19 are a common genetic cause of epilepsy. As the gene was only identified in 2008, we are rapidly learning about this condition as more people are being diagnosed.
It is crucial that we capture as many individuals as possible with PCDH19 pathogenic variants (including those not reported in the medical literature). This includes females as well as males, so we can build a more comprehensive understanding of this condition.