Triplication of the Gene as a Novel Disease Mechanism Leading to Epileptic Encephalopathy Resembling Loss-of-Function Pathogenic Variants.

BACKGROUND/OBJECTIVES: Developmental and epileptic encephalopathy 9 (DEE9) (MIM #300088) affects heterozygous females and males with somatic pathogenic variants, while male carriers with hemizygous pathogenic variants are clinically unaffected. There are hundreds of pathogenic single nucleotide variants in the gene reported in the literature, which lead to the loss of function of the PCDH19 protein. To date, no phenotypes associated with overexpression or copy number gains have been described in this gene.

METHODS AND RESULTS

We present a female patient with a de novo triplication in the Xq21.3-q22.1 chromosomal region, which includes the gene, which implies an unbalanced dose gain. This patient displayed a phenotype of epileptic encephalopathy compatible with DEE9. By comparison, another male patient with a similar duplication showed mild developmental delay and autism but never developed epilepsy.

CONCLUSIONS

Here, we propose the dose gain of as a new pathogenic mechanism that results in a phenotype similar to that found in patients with loss-of-function variants in , when present in a heterozygous state.