# Complexity of Inheritance of Pathogenic Mutations Associated with Epilepsy in Consanguine Families from Pakistan

## TL;DR

This study explores how pathogenic mutations linked to epilepsy are inherited in consanguine families from Pakistan, revealing complex patterns and new insights into rare recessive genes.

## Contribution

The study identifies new recessive epilepsy genes and highlights the importance of analyzing exome data with multiple inheritance models.

## Key findings

- Pathogenic mutations in both classical dominant and rare recessive epilepsy genes were identified.
- GALR2 is potentially a new gene associated with recessive epilepsy.
- A homozygous TRAF3IP1 mutation did not contribute to the phenotype, likely due to stop-codon read-through.

## Abstract

Background/Objectives: Consanguine families are helpful to identify recessive candidate genes for inherited diseases, but can also show an unusual inheritance pattern of pathogenic mutations. In this case series, we demonstrate this in five consanguine families with epilepsy from Pakistan. Methods: We performed whole exome sequencing of respective index patients, analyzed the data using two different models for inheritance of mutations and determined the segregation pattern of relevant mutations in the families by bi-directional Sanger sequencing. Results: Apart from mutations in classical dominant epilepsy genes (TSC2, DEPDC5, and CACNA1I), pathogenic mutations in rare recessive epilepsy-related genes (PGAP2, NOVA2, and CCDC88C) were also identified. Interestingly, we were able to provide evidence that GALR2 is potentially an additional gene associated with a recessive form of epilepsy. In one family, a homozygous ‘pathogenic’ TRAF3IP1 p. Gly387* nonsense mutation was identified, which, most probably due to stop-codon read-through, did not contribute to the phenotype. Conclusions: Our case series of consanguine families with epilepsy exemplifies the inheritance pattern of mutations in rare recessive epilepsy genes, and shows that mutations in classical epilepsy genes showing dominant or sporadic inheritance can also be relevant. That requires the analysis of whole exome data on the basis of different inheritance models.