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Male patients affected by mosaic PCDH19 mutations: five new cases
I M de Lange1, P Rump2, R F Neuteboom3
1Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Lundlaan 6, 3584CG, Utrecht, The Netherlands. i.m.delange-2@umcutrecht.nl.
Abstract:
Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years).
Insights
Pathogenic variants in the PCDH19 gene cause epilepsy and intellectual disability (ID) in females and mosaic males. This study describes five new mosaic male patients, expanding knowledge of this rare genetic disorder.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Pathogenic variants in the PCDH19 gene are linked to epilepsy, intellectual disability (ID), and behavioral issues.
- The PCDH19-related disorder primarily affects heterozygous females and mosaic males due to a cellular interference mechanism.
- Previously, only four affected mosaic males with PCDH19 gene variants had been documented.
Purpose of the Study:
- To report on five additional mosaic male patients with PCDH19 gene variants.
- To further characterize the clinical phenotype of PCDH19-related disorders in males.
- To compare the male phenotype with the established female phenotype.
Main Methods:
- Genetic analysis using custom-targeted next-generation sequencing gene panels for epilepsy genes.
- Clinical data collection from medical records of affected individuals.
- Identification of likely pathogenic variants in the PCDH19 gene in mosaic males.
Main Results:
- Five mosaic male patients with likely pathogenic PCDH19 variants were identified.
- Three patients presented with epilepsy, developmental delay, and behavioral problems.
- Clinical features in these males largely mirrored the known female phenotype, including early-onset seizures and fever sensitivity.
Conclusions:
- This study expands the cohort of known mosaic males with PCDH19 gene variants.
- The findings reinforce the phenotypic similarity between males and females with PCDH19-related disorders.
- The results provide insights into the long-term clinical course of the disorder in males up to adolescence.
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