NGS-Based Identification of Two Novel PCDH19 Mutations in Female Patients with Early-Onset Epilepsy

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Developmental and epileptic encephalopathy-9 (DEE9) is an X-linked disorder caused by PCDH19 gene mutations, affecting heterozygous females and mosaic males.
• Transmitting males are typically unaffected, but the inheritance pattern and penetrance in females require further investigation.

Purpose of the Study:

• To investigate PCDH19 mutations in patients with epilepsy.
• To identify novel mutations and understand the genotype-phenotype spectrum of PCDH19-related epilepsy.
• To explore the phenomenon of reduced penetrance in DEE9.

Main Methods:

• Next Generation Sequencing (NGS)-based panel and exome sequencing were used to screen 165 epilepsy patients.
• Illumina technology was employed for sequencing.
• Sanger sequencing and X chromosome inactivation tests were performed for mosaicism examination.

Main Results:

• Five unrelated female probands with DEE9 had PCDH19 mutations identified, including three point mutations, one indel, and one deletion.
• Two novel de novo pathogenic mutations (c.1152_1180del and c.830_831delinsAA) were discovered.
• Inherited mutations were found in two asymptomatic mothers and one affected father, with asymptomatic mothers carrying PCDH19 mutations (c.1682C>T and c.1711G>T) without exhibiting symptoms.

Conclusions:

• The findings support the occurrence of reduced penetrance in DEE9.
• This study expands the known genotype-phenotype spectrum for PCDH19-related epilepsy.
• The identification of novel mutations and the confirmation of reduced penetrance provide crucial insights into DEE9 genetics.