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

<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: Apart from mutations in classical dominant epilepsy genes (<i>TSC2</i>, <i>DEPDC5</i>, and <i>CACNA1I</i>), pathogenic mutations in rare recessive epilepsy-related genes (<i>PGAP2</i>, <i>NOVA2</i>, and <i>CCDC88C</i>) were also identified. Interestingly, we were able to provide evidence that <i>GALR2</i> is potentially an additional gene associated with a recessive form of epilepsy. In one family, a homozygous 'pathogenic' <i>TRAF3IP1</i> p. Gly387* nonsense mutation was identified, which, most probably due to stop-codon read-through, did not contribute to the phenotype. <b>Conclusions</b>: 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.